CN100384836C - Novel cyclic amide derivatives - Google Patents

Novel cyclic amide derivatives Download PDF

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CN100384836C
CN100384836C CNB01808687XA CN01808687A CN100384836C CN 100384836 C CN100384836 C CN 100384836C CN B01808687X A CNB01808687X A CN B01808687XA CN 01808687 A CN01808687 A CN 01808687A CN 100384836 C CN100384836 C CN 100384836C
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compound
methyl
obtains
isoindoline
piperidin
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CN1426405A (en
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山边晴子
奥山昌弘
中尾朗
大泉充
斋藤健一
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Mitsubishi Pharma Corp
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Abstract

Novel compounds of the general formula (I) acting as ligands for the binding sites of sigma receptors; and drugs containing the compounds as the active ingredient, wherein X is alkyl, aryl, a heterocyclic group, or the like; Q is -CH2-, -CO-, -O-, -CH(OR7)- (wherein R7 is hydrogen, alkyl, or the like), or the like; n is an integer of 0 to 5; R1 and R2 are each hydrogen, alkyl, or the like; and B is a group represented by the general formula (II) or (III) (wherein R3, R4, R5 and R6 are each hydrogen, halogeno, alkoxy, or the like; m is 1 or 2; and the ring (IV) is an aromatic heterocycle).

Description

Novel cyclic amide derivatives
Technical field
The present invention relates to a kind of novel cpd that sigma-receptor/combining site is worked as part and contain the medicine of this compound as effective constituent.
Background technology
In recent years sigma-receptor/the combining site of the brain of Que Rening is important target (J.M.Walker, W.D.Bowen, F.O.Walker, R.R.Matsumoto, B.de Costa and K.C.Rice for the antipsychotic drug of the side effect of a kind of antipsychotic drug with d2 dopamine receptor antagonistic action that can eliminate present utilization of exploitation, " pharmacology comment " (Pharmacological Reviews), 42, pp.355～402,1990; G.Debonnel, " psychosis Journal of Neuroscience " (J.Psychiatr.Neurosci.), 18,4, pp.157～172,1993; G.Debonnel and C.deMontigny, " life science " (Life Sciences), 58,9, pp.721～734,1996).In addition, some data had also once been reported, the hint sigma ligands is (in this specification sheets, sometimes claim " sigma-receptor part ") and acceptor come regulating command conduction system (P.J.Brent, H.Saunders and P.R.Dunkley by the intravital calcium contents of control cynapse, " neuroscience communication " (Neurosci.Lett.), 211, pp.138～142,1996).
The term of Shi Yonging " acceptor " is meant film mating type acceptor and other combining site herein, two kinds of sigma-receptor subclass have been confirmed to exist at least, be σ 1 and σ 2, classification (R.Quirion, W.D.Bowen, Y.Itzhak, J.L.Junien, J.M.Musacchio, R.B.Rothman, T.P.Su, W.Tam and the D.P.Taylor of σ combining site have been proposed, " TiPS ", 13, pp.85～86,1992).The feature of σ 1 combining site is, to the affinity height of (+) benzomorphans such as haloperidol, two-o-tolyl guanidine (DTG) and (+) pentazocine, on the other hand, the feature of σ 2 combining sites is, to the affinity height of haloperidol and DTG, and low to the affinity of (+) benzomorphans.
As if σ 1 part has effect to gi tract, and then σ 1 position also mediates the restraining effect that the acetylcholine receptor phosphoinositide of the muscarine sample that causes for sigma ligands is replied.σ 1 combining site does not exist only in the brain, and be present in (Y.Lin, B.B.Whitlock, J.A.Pultz and S.A.Wolfe Jr, " J.Neuroimmunol. ", 58 on the spleen cell, pp.143～154,1995), this sigma ligands has often suppressed immunity system (H.H.Garza, S.Mayo, W.D.Bowen, B.R.DeCosta and D.J.J.Carr, " immunology " (J.of Immunology), 151,9, pp.4672～4680,1993).
σ 2 combining sites are present in the liver (A.E.Bruce, S.B.Hellewell and W.D.Bowen, " neuroscience digest " (Neurosci.Abstr.), 16,370,1990 in a large number; A.S.Basile, I.A.Paul and B.DeCosta, " European pharmacology magazine molecular medicine part " (Eur.J.Pharmacol.Mol.Pharm.Sect.), 227, pp.95～98,1992; C.Torrence-Campbell and W.D.Bowen, " European pharmacology magazine " (Eur.J.Pharmacol.), 304, pp.201～210,1996), (W.D.Bowen, G.Feinstein and J.S.Orringer, " social neuroscience digest " are (Soc.Neurosci.Abstr.) in the kidney, 18,456, digest 195.8,1992) and heart interior (M.Dumont and S.Lemaire, " European pharmacology magazine " (Eur.J.Pharmacol.), 209, pp.245～248,1991).
σ 2 combining sites in the brain are present in hypothalamus, cerebellum and marrow bridge, the oblongata (ponsmedulla).In hippocampus in rat brain, frontal lobe and the occipital lobe, to have in large quantities also than σ 1 combining site that (D.J.Mc Cann, A.D.Weissmann and T.P.Su, " social neuroscience digest " are (Soc.Neurosci.Abstr.), 18,22, digest 16.5,1992).In the hippocampus synaptosome of cavy, also existence usefulness [ 3H] σ 2 combining sites (D.W.Bonhaus, D.N.Loury, L.B.Jakeman, Z.TO, A.DeSouza, R.M.Eglen and E.H.F.Wong, " J.Pharmacol.Exp.Ther. ", 267,2, pp.961～970,1993) of BIMU selected marker.The relation of σ 2 combining sites and cortex and edge system, to the availability that is used for the treatment of psychotic compound support (D.C.Mash and C.P.Zabetian, " cynapse " (Synapse), 12, pp.195～205,1992).
σ 2 combining sites are considered to relevant (R.R.Matsumoto, M.K.Hemstreet, N.L.Lai, A.Thurkauf, B.R.DeCosta, K.C.Rice, S.B.Hellewell, W.D.Bowen and J.M.Walker with motion effect, particularly myodystonia, " pharmacology biochemical behavior " (Pharmacol.Biochem.Behav.), 36, pp.151～155,1990).But, do not have to find the handicapped primates models show of extrapyramidal tract is gone out evidence (L.T.Meltzer, C.L.Christoffersen, K.A.Serpa, T.A.Pugsley, A.Razmpour and the T.G.Heffner of this effect, " neuropharmacology " (Neuropharmacology), 31,9, pp.961～967,1992).
The haloperidol that belongs to the anti-spiritual medicine of effective clinically Dopamine HCL functionality, these two kinds of σ subclass are demonstrated high affinity, and the reduced form meta-bolites that acts on the haloperidol of central nervous system is compared with haloperidol, have affinity and selectivity (J.C.Jaen, B.W.Caprathe, T.A.Pugsley, L.D.Wise and the H.Akunne to σ 2 acceptors also better than dopamine D 2, " medical chemistry magazine " (J.Med.Chem.), 36, pp.3929～3936,1993).In fact, owing to can not utilize the medicament of selection, thereby can not illustrate pharmacological meaning, distribution and the function thereof of σ 2 combining sites.On the other hand, studies show that in recent years, σ 2 positions play a part to regulate ileum function (G.G.Kinney, E.W.Haris, R.Ray and T.J.Hudzik, " European pharmacology magazine " (Europ.J.Pharmacol.), 294, pp.547～553,1995).These data suggest selectivity σ 2 parts are useful to the treatment of irritable bowel syndrome.
This sigma ligands has been opened in flat 9-302607 communique, the flat 10-508826 communique of special table etc. open the spy, but does not have record fully with the cyclic amide derivative headed by isoindoline-1-ketone.
On the other hand, as having the compound of similar structures, disclose in the flat 7-506107 communique of special table with general formula of the present invention (I)
And the 4-imide methyl isophthalic acid of hydrochloride etc.-[2 '-phenyl-2 '-oxoethyl] piperidines.But these compounds are put down in writing as thrombotonin 2 antagonists, do not know fully whether these compounds have the effect as sigma ligands.And then this compound with phthalimide-based has problem probably in security.
Summary of the invention
Problem of the present invention provides a kind of novel cpd that the σ combining site is had good affinity.In addition, another problem of the present invention provides a kind of useful medicine of disease that compound with above-mentioned feature treats and/or prevents as effective constituent, for the neuroregulation effect by sigma ligands that contains.
Present inventors have carried out deep research in order to solve above-mentioned problem, found that, the compound group of following formula (I) expression has high affinity to the σ combining site, inhibition constant K i to σ 1 and/or σ 2 is little, but also find, these compounds have the selective binding distribution plan of known compound different from the past fully, and are useful for the disease that the neuroregulation effect by sigma ligands treats and/or prevents.The present invention finishes with regard to being based on these discoveries.
That is, main idea of the present invention provides compound or its salt or their hydrate or the solvate of following formula (I) expression:
[in the formula,
X represents alkyl, cycloalkyl substituted alkyl, aryl substituted alkyl, aryl substituted alkenyl base, aryl substituted alkynyl, monocycle or polycyclic cycloalkyl, aryl, heterocyclic radical or replacement or the unsubstituted amino that can replace with alkyl;
Q is with-CH 2-,-CO-,-O-,-S-,-CH (OR 7)-,-C (=CH 2)-or-C (=NR 8The group of)-expression (in the formula, R 7Be hydrogen atom, alkyl, hydroxyalkyl or acyl group, R 8Be hydroxyl, alkoxyl group, aralkoxy, acyloxy, amido or alkoxycarbonyl amido);
N represents 0～5 any integer;
R 1And R 2Represent hydrogen atom or alkyl independently of one another, perhaps R 1And R 2Represent alkylidene group together;
B represents following any group:
Figure C0180868700082
(in the formula, R 3, R 4, R 5And R 6Expression independently of one another is selected from the substituting group of hydrogen atom, halogen atom, nitro, alkyl, haloalkyl, hydroxyl, alkoxyl group Z, halogenated alkoxy and cyano group);
M represents 1 or 2;
Figure C0180868700083
Expression can have that substituent to contain 1 or 2 heteroatomic annular atoms numbers be 5 or 6 heteroaromatic)].
In the 1st preferred embodiment, the present invention relates to the compound or its salt of a kind of formula (I) expression or their hydrate,
Figure C0180868700084
In the formula,
X represents C1～6 alkyl, C1～6 alkyl that aryl replaces, unsubstituting aromatic yl or C2～6 alkenyls that replaced by the aryl that halogen atom replaces, unsubstituting aromatic yl or C2～6 alkynyls that replaced by the aryl that halogen atom replaces, C3～8 cycloalkyl, replace or unsubstituted C6～14 aryl, replacement or unsubstituted, contain and be selected from Sauerstoffatom, 1～4 heteroatoms of sulphur atom and nitrogen-atoms is as 5～10 element heterocycle bases of ring atom, perhaps replace or unsubstituted amino, wherein, the C6 of above-mentioned replacement～14 aryl, substituting group on 5～10 element heterocycle groups that replace can be halogen atom, nitro, C1～6 alkyl, phenyl C1～6 alkyl, halo C1～6 alkyl, hydroxyl, C1～6 alkoxyl groups, phenyl C1～6 alkoxyl groups, C1～6 alkyl that aryl replaces, halo C1～6 alkoxyl groups, unsubstituted phenyl, the phenyl that halogen atom or C1～6 alkoxyl groups replace, phenoxy group, amino, acyl group, C1～6 alkylaminos, C1～6 alkanoylamino, the substituting group on the amino of described replacement can be C1～6 alkyl, do not replace C6～14 aryl, by C6～14 aryl of halogen atom or C1～6 alkoxyl groups replacement;
Above-mentioned aryl except C6～14 aryl is that atomicity is the aryl of 6～14,1～3 rings, and in addition, for the aryl of 2～3 rings, what the part of ring was hydrogenated is also included within this aryl;
Q is-CO-;
N represents integer 1;
R 1And R 2Represent hydrogen atom or C1～6 alkyl independently of one another;
B represents following radicals:
Figure C0180868700091
In the formula, R 3, R 4, R 5And R 6Represent the substituting group from hydrogen atom, halogen atom, nitro, C1～6 alkyl, halo C1～6 alkyl, hydroxyl, C1～6 alkoxyl groups, halo C1～6 alkoxyl groups and cyano group, selected independently of one another;
M represents 1 or 2.
In the 2nd preferred embodiment, further the X in preferred the 1st embodiment is C1～6 alkyl, aryl replaces C1～6 alkyl, aryl replaces C2～6 alkenyls, aryl replaces C2～6 alkynyls, replace or unsubstituted C6～14 aryl, monocycle C3～8 cycloalkyl, contain and be selected from Sauerstoffatom, 1～4 heteroatoms of sulphur atom and nitrogen-atoms is as 5～10 Yuans monocycle heterocyclic radicals of ring atom, contain and be selected from Sauerstoffatom, sulphur atom and nitrogen-atoms 1 or 2 heteroatomic atomicities are 8～10 two ring property heteroaryls, perhaps use the amino of C1～6 alkyl or C6～14 aryl replacement;
Above-mentioned aryl except C6～14 aryl is that atomicity is the aryl of 6～14,1～3 rings, and in addition, for the aryl of 2～3 rings, what the part of ring was hydrogenated is also included within this aryl;
N is an integer 1;
R 1And R 2Be hydrogen atom;
R 3, R 4, R 5And R 6Be the substituting group of from hydrogen atom, halogen atom, nitro, C1～6 alkyl, halo C1～6 alkyl, hydroxyl, C1～6 alkoxyl groups, halo C1～6 alkoxyl groups and cyano group, selecting independently of one another;
M is 1 or 2.
In the 3rd preferred embodiment, further the X in preferred the 2nd embodiment is for replacing or unsubstituted phenyl, contain and be selected from Sauerstoffatom, 1～4 heteroatoms of sulphur atom and nitrogen-atoms is 5 or 6 monocycle heterocyclic radical as the atomicity of ring atom, perhaps contain and be selected from Sauerstoffatom, sulphur atom and nitrogen-atoms 1 or 2 heteroatomic atomicities are 8～10 two ring property heteroaryls, wherein, the substituting group on the phenyl of replacement is from halogen atom, C1～6 alkyl, halo C1～6 alkyl, the substituting group of selecting in C1～6 alkoxyl groups and halo C1～6 alkoxyl groups more than 1 or 2.
In the 4th preferred embodiment, further the B in preferred the 2nd embodiment represents with following formula:
Figure C0180868700101
In the formula, R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is the substituting group selected from hydrogen atom, halogen atom, nitro, C1～6 alkyl, hydroxyl, C1～6 alkoxyl groups and cyano group.
In the 5th preferred embodiment, further the X in preferred the 1st embodiment is for replacing or unsubstituted phenyl, and wherein substituting group is the substituting group of selecting from halogen atom and C1～6 alkoxyl groups more than 1 or 2;
N is 1;
R 1And R 2Be all hydrogen atom;
R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is hydrogen atom, halogen atom or C1～6 alkoxyl groups;
M is 1 or 2.
From other viewpoint, the invention provides a kind of medicine that contains the material from above-claimed cpd and salt and their hydrate and solvate, selected as effective constituent, as its preferred scheme, the invention provides the useful above-mentioned medicine of disease (for example central nervous system disease, gastrointestinal illness or cardiovascular system diseases etc.) that treats and/or prevents for neuroregulation effect by sigma ligands.In addition, the present invention also provides the sigma ligands that is made of the material of selecting from above-claimed cpd and salt and their hydrate and solvate.
And then, from another viewpoint, the present invention also provides the method that treats and/or prevents of the use of material a kind of above-mentioned medicine that is used for making above-mentioned medicine, preferred medical composition form, that select from above-claimed cpd and salt thereof and their hydrate and solvate and the neuroregulation effect by sigma ligands, and this method comprises the material that will select from above-claimed cpd and salt and their hydrate and solvate significant quantity is to the step of the mammal administration that comprises the people.
The preferred plan that carries out an invention
In the above-mentioned general formula (I), X represents alkyl, cycloalkyl substituted alkyl, aryl substituted alkyl, aryl substituted alkenyl base, aryl substituted alkynyl, monocycle or polycyclic cycloalkyl, aryl, heterocyclic radical or replacement or the unsubstituted amino that can replace with alkyl.
The term that uses in this specification sheets " alkyl " perhaps for containing alkyl as the employed term of the group of integrant " alkyl ", comprises for example a straight chain shape or a catenate alkyl of 1～6 of carbonatoms, 1～4 of preferred carbonatoms.More particularly, as alkyl, can use methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl and n-hexyl etc.
The occasion that is called " alkyl " in this specification sheets; when not specializing; comprise having substituent occasion more than 1 or 2, this substituting group comprises halogen atom, nitro, cycloalkyl, aryl, aryloxy, heteroaryl, hydroxyl, alkoxyl group, halogenated alkoxy, carboxyl, carbalkoxy, replacement or unsubstituted amino, acyl group or cyano group etc.As these substituting groups, preferably can use group described later.
The term that uses in this specification sheets " cycloalkyl " or for containing cycloalkyl as the employed term of the group of integrant " cycloalkyl ", comprise that for example atomicity is 3～8, preferably atomicity is about 3～6 cycloalkyl (under the occasion that does not specialize, being the cycloalkyl of monocycle).Can have 1 or 2 alkyl on the ring of these cycloalkyl.More particularly, as cycloalkyl, can use for example cyclopropyl, methyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, Dimethylcyclohexyl etc.As the polycyclic cycloalkyl, can enumerate atomicity and be 5～12 multi-ring alkyl, for example norcamphyl and adamantyl etc. preferably can use adamantyl.
As the cycloalkyl substituted alkyl, can enumerate for example cyclopropyl methyl, methyl cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl propyl group, cyclobutylmethyl, cyclobutyl ethyl, cyclopentyl-methyl, cyclohexyl methyl or Dimethylcyclohexyl methyl etc.
The term that uses in this specification sheets " aryl " or for containing aryl as the employed term of the group of integrant " aryl " comprises that for example atomicity is the aryl of about 6～14,1～3 rings.For example, except phenyl, 1-naphthyl, 2-naphthyl, can use phenanthryl, anthryl etc.In addition, that the part of ring is hydrogenated, for example 5,6,7 for the aryl of 2～3 rings, 8-tetralyl etc. is also included within the aryl.
The term that uses in this specification sheets " alkenyl " is for example alkenyl of the straight or branched of carbonatoms 2～6, preferred carbonatoms 3～6, comprise contain more than 1 or 2, the alkenyl of preferred 1 two key.As alkenyl, can use for example 1-propenyl, allyl group, pseudoallyl, 1-butylene base, 3-butenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl or 2-hexenyl etc.The two keys that exist in the alkenyl can be cis or trans any configuration.
Term " alkynyl " comprises the alkynyl of the straight or branched of 2～6 of carbonatomss, 3～6 of preferred carbonatomss.Can enumerate for example 2-propynyl, 3-butynyl, 4-pentynyl or 5-hexin base etc.
As " heterocyclic radical ", can use and contain 1～4 heteroatoms being selected from Sauerstoffatom, sulphur atom and nitrogen-atoms heterocyclic radical as 1～3 ring of 5～10 Yuans of ring atom.For example, can use furyl (furan nucleus), benzofuryl (cumarone ring), isobenzofuran-base (isobenzofuran ring), thienyl (thiphene ring), benzothienyl (thionaphthene ring), pyrryl (pyrrole ring), imidazolyl (imidazole ring), pyrazolyl (pyrazoles ring), thiazolyl (thiazole ring), benzothiazolyl (benzothiazole ring), isothiazolyl (isothiazole ring), benzisothiazole base (benzisothiazole ring), triazolyl (triazole ring), tetrazyl (tetrazole ring), pyridyl (pyridine ring), pyrazinyl (pyrazine ring), pyrimidyl (pyrimidine ring), pyridazinyl (pyridazine ring), indyl (indole ring), pseudoindoyl (isoindole ring), benzimidazolyl-(benzoglyoxaline ring), purine radicals (purine skeleton), quinolyl (quinoline ring), isoquinolyl (isoquinoline 99.9 ring), dihydro-isoquinoline base (dihydro-isoquinoline ring), phthalazinyl (phthalazines ring), naphthyridinyl (naphthyridines ring), quinoxalinyl (quinoxaline ring), cinnolines base (cinnolines ring), pteridyl (pteridine ring) oxazolyl (oxazole ring) benzoxazolyl (benzoxazole ring isoxazolyl (isoxazole ring)), benzoisoxazole base (benzoisoxazole ring), furazan base (furazan ring) oxazinyl (oxazine ring) etc.In addition, the ring that also can use the part of these rings to be hydrogenated, for example pyrrolidyl (pyrrolidine ring), imidazolidyl (imidazolidine ring), piperidyl (piperidine ring), piperazinyl (piperazine ring), morpholinyl (morpholine ring) etc.Wherein, as heterocyclic radical of the present invention, preferably containing 1 or 2 heteroatomic atomicities and be 5～7 monocycle heterocyclic radical or containing 1 or 2 heteroatomic atomicities is 8～10 two ring property heteroaryls.
The occasion that is called " cycloalkyl ", " aryl ", " heterocyclic radical " or " heteroaryl " in this specification sheets; when not specializing; comprise on the ring of cycloalkyl, aryl, heterocyclic radical or heteroaryl having substituent occasion more than 1 or 2, this substituting group comprises halogen atom, nitro, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, carboxyl, carbalkoxy, phenyl, phenoxy group, replacement or unsubstituted amino, acyl group or cyano group etc.As these substituting groups, preferably can use the group or the group described later of above-mentioned explanation.
As replacing or unsubstituted amino, can enumerate for example amino, be amidos such as alkylamino, alkyl amido or aryl-amino-carbonyl, arylalkylamino or the alkyl sulfonyl-amino etc. of alkyl monosubstituted amino or dialkyl amido.More particularly, can enumerate alkylaminos such as monomethyl amino, dimethylamino, ethylamino, diethylamino, methylethyl amino, propyl group amino, dipropyl amino, butyl amino, amyl group amino, hexyl amino; Kharophen, trifluoroacetamido, propionamido, benzamido, to amidos such as methoxybenzoyl amino; Benzylamino, to aryl alkyl aminos such as methoxy-benzyl amino; Alkyl sulfonyl-aminos such as methyl sulphonyl amino, ethylsulfonyl amino, n-propyl sulfuryl amino, n-hexyl sulfuryl amino.
Be called in this specification sheets under the occasion of " halogen atom " or " halo ", as halogen atom can use fluorine atom, chlorine atom, bromine atoms or iodine atom any.The term that uses in this specification sheets " haloalkyl " comprises for example a methyl fluoride, difluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl group, a chloromethyl, dichloromethyl, trichloromethyl etc., as preferred example, comprises trifluoromethyl.
The term that uses in this specification sheets " alkoxyl group " perhaps for containing alkoxyl group as the employed term of the group of integrant " alkoxyl group ", comprises for example alkoxyl group of the straight or branched of 1～6 of carbonatoms, 1～4 of preferred carbonatoms.More particularly, as alkoxyl group, can use methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy or positive hexyloxy etc.As halogenated alkoxy, can use for example trifluoromethoxy, trifluoro ethoxy, a chlorine methoxyl group, trichlorine methoxyl group etc.
As carbalkoxy, can use the carbalkoxy that for example constitutes by above-mentioned alkoxyl group, more particularly, can use methoxycarbonyl, ethoxycarbonyl, the positive third oxygen carbonyl, the different third oxygen carbonyl etc.
As acyl group, can enumerate alkyloyl (alkyl-carbonyl, halogenated alkyl carbonyl etc.), aryl carbonyl, heteroaryl carbonyl etc.More particularly, can use formyl radical, ethanoyl, propionyl, trifluoromethyl carbonyl, pentafluoroethyl group carbonyl, benzoyl, to anisoyl, 3-pyridyl carbonyl etc.
As X of the present invention; be preferably alkyl; the aryl substituted alkyl; aryl substituted alkenyl base; the aryl substituted alkynyl; aryl; the monocycle cycloalkyl; the monocycle heterocyclic radical; contain 1 or 2 heteroatomic atomicities and be 8～10 two ring property heteroaryls; the perhaps amino that replaces with alkyl or aryl; more preferably replacement or unsubstituted phenyl (as this substituting group, can be enumerated for example from halogen atom; alkyl; haloalkyl; alkoxyl group; halogenated alkoxy; aralkyl; aralkoxy; phenyl; phenoxy group; furyl; acyl group; amino; alkylamino; amido; the group of selecting in nitro and the cyano group more than 1 or 2); atomicity is 5 or 6 monocycle heterocyclic radical; perhaps contain 1 or 2 heteroatomic atomicities and be 8～10 two ring property heteroaryls.
As X of the present invention, preferred group for replace or unsubstituted phenyl (as this substituting group, the group of preferably from halogen atom, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy and cyano group, selecting more than 1 or 2, the substituting group of more preferably from halogen atom and alkoxyl group, selecting more than 1 or 2), especially preferably to fluorophenyl.
In the above-mentioned general formula (I), Q is with-CH 2-,-CO-,-O-,-S-,-CH (OR 7)-,-C (=CH 2)-or-C (=NR 8The group of)-expression.R 7Be hydrogen atom, alkyl, hydroxyalkyl or acyl group, be preferably hydrogen atom, low alkyl group or ethanoyl, be preferably hydrogen atom or ethanoyl especially.In addition, R 8Be hydroxyl, alkoxyl group, aralkoxy, acyloxy, amido or alkoxycarbonyl amido, preferably can enumerate hydroxyl, alkoxyl group or amido.As R 8, preferred especially hydroxyl or kharophen.
As Q of the present invention, preferably with-CH 2-,-CO-,-O-,-C (=NOH)-or-CH (OR 7The group of)-expression is more preferably with-CH 2-,-CO-,-O-or-group of CH (OH)-expression.Be preferably especially-CO-.
In the above-mentioned general formula (I), n represents 0～5 integer, is preferably 0～4 integer.More preferably n is 1～3 integer, is preferably 1 especially.
In the above-mentioned general formula (I), R 1And R 2Represent hydrogen atom or alkyl independently of one another, perhaps R 1And R 2Represent alkylidene group together.Wherein, preferred R 1And R 2Be hydrogen atom or alkyl independently of one another, especially preferably be all hydrogen atom.
Among the B of above-mentioned general formula (I), R 3, R 4, R 5And R 6Represent the substituting group from hydrogen atom, halogen atom, nitro, alkyl, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy and cyano group, selected independently of one another.Wherein, preferred R 3, R 4, R 5And R 6Be the substituting group of selecting in hydrogen atom, halogen atom, nitro, alkyl, hydroxyl, alkoxyl group and the cyano group, more preferably R independently of one another 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is the substituting group selected from hydrogen atom, halogen atom, nitro, alkyl, hydroxyl, alkoxyl group and cyano group.Further preferred R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is the substituting group selected, particularly preferably is R from hydrogen atom, halogen atom, alkoxyl group and cyano group 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methoxyl group or cyano group.In addition, m represents 1 or 2, is preferably 1.
In the above-mentioned group that B represents,
Figure C0180868700161
Expression can have that substituent to contain 1 or 2 heteroatomic atomicities be 5 or 6 heteroaromatic.Wherein, be preferably and have the heteroaromatic of selecting in substituent furan nucleus, thiphene ring and the pyridine ring, more preferably unsubstituted thiphene ring or furan nucleus.
In the compound that comprises in the above-mentioned general formula (I),, can enumerate as preferred compound group:
(1) X is alkyl, aryl substituted alkyl, aryl substituted alkenyl base, aryl substituted alkynyl, aryl, monocycle cycloalkyl, monocycle heterocyclic radical, to contain 1 or 2 heteroatomic atomicities be 8～10 two ring property heteroaryl or replacement or unsubstituted amino, and Q is with-CH 2-,-CO-,-O-,-S-,-CH (OR 7)-or-C (=NR 8The group of)-expression (in the formula, R 7Expression hydrogen atom, alkyl or acyl group, R 8Expression hydroxyl, alkoxyl group or amido), n is any integer of 0～4, R 1And R 2Be hydrogen atom or alkyl independently of one another, R 3, R 4, R 5And R 6Be the substituting group of selecting from hydrogen atom, halogen atom, nitro, alkyl, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy and cyano group independently of one another, m is 1 or 2,
For having the heterocyclic compound of selecting in substituent furan nucleus, thiphene ring and the pyridine ring.
And then, as preferred compound group, can enumerate:
(2) X is alkyl, aryl substituted alkyl, aryl substituted alkenyl base, aryl substituted alkynyl, aryl, monocycle cycloalkyl, monocycle heterocyclic radical, to contain 1 or 2 heteroatomic atomicities be 8～10 two ring property heteroaryls or the amino that replaces with alkyl or aryl, R 1And R 2Be all hydrogen atom, R 3, R 4, R 5And R 6Be the substituting group of selecting from hydrogen atom, halogen atom, nitro, alkyl, hydroxyl, alkoxyl group and cyano group independently of one another, m is 1 or 2,
Figure C0180868700163
Compound for (1) that can have substituent furan nucleus, thiphene ring or pyridine ring;
(3) X is for replacing or unsubstituted phenyl (the substituting group 1 or 2 or more of this substituting group for selecting from halogen atom, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy and cyano group), atomicity are 5 or 6 monocycle heterocyclic radical or to contain 1 or 2 heteroatomic atomicities be 8～10 two ring property heteroaryls, R 1And R 2Be all hydrogen atom, R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is the substituting group selected from hydrogen atom, halogen atom, nitro, alkyl, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy and cyano group, m is 1 or 2,
Figure C0180868700171
For having the compound of the heterocyclic of selecting in substituent furan nucleus, thiphene ring and the pyridine ring (1);
(4) Q is-CH 2-,-CO-,-O-,-C (=NOH)-or-CH (OR 7In)-(the formula, R 7Be hydrogen atom, alkyl or acyl group),
B represents with following formula:
Figure C0180868700172
(in the formula, R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is the substituting group selected from hydrogen atom, halogen atom, nitro, alkyl, hydroxyl, alkoxyl group and cyano group), n is the compound of 1 (2) or (3);
(5) X is for replacing or unsubstituted phenyl (the substituting group 1 or 2 or more of this substituting group for selecting from halogen atom and alkoxyl group), and Q is-CH 2-,-CO-,-O-or-CH (OH)-, n is any integer of 1～3, R 1And R 2Be all hydrogen atom, R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is hydrogen atom, halogen atom or alkoxyl group, m is 1 or 2,
Figure C0180868700173
Compound for thiphene ring or furan nucleus.
As particularly preferred compound group, can enumerate:
(6) X is for replacing or unsubstituted phenyl, naphthyl, the tertiary butyl, cyclohexyl, replacement or unsubstituted pyrryl, piperidyl, benzoisoxazole base, benzo dioxole, tetrahydric quinoline group, indolinyl or replacement or unsubstituted phenylamino, and Q is-CH 2-,-CO-,-O-,-S-,-CH (OH)-or-C (=NOH)-, n is any integer of 0～2, R 1And R 2Be all hydrogen atom, R 3, R 4, R 5And R 6In 3 be hydrogen atom,
Remaining one is getting of selecting from hydrogen atom, fluorine atom, chlorine atom, bromine atoms and methoxyl group
Dai Ji, m are 1 or 2,
Figure C0180868700181
Compound for furan nucleus or thiphene ring;
(7) X is to fluorophenyl, and Q is-CH 2-,-CO-,-O-or-CH (OH)-, n is 1, R 1And R 2Be all hydrogen atom, R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is hydrogen atom, halogen atom or methoxyl group, m is 1 compound;
(8) Q is-compound of CO-(7);
(9) R 3, R 4, R 5And R 6It all is the compound of (8) of hydrogen atom;
(10) R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is the compound of (8) of halogen atom;
(11) X is to fluorophenyl, and Q is-CO-, and n is 1,
Figure C0180868700182
Compound for (6) of furan nucleus or thiphene ring.
The concrete example of the particularly preferred compound of the present invention shown in the following table, but compound of the present invention is not subjected to their qualification.In the compound group shown in the following table, R 1And R 2Be all hydrogen atom.In the table, for example, the mark of relevant X " p-F-Ph ", expression X is to fluorophenyl, other mark is too.In addition, " Bu " expression butyl or butylidene, " Pr " expression propyl group or propylidene, " Et " expression ethyl or ethylidene, " Ac " represents ethanoyl, " " " the expression group identical with last hurdle.
Again, table-1 illustrates the compound that B is a following radicals:
Table-2 illustrates the compound that B is a following radicals:
Figure C0180868700184
In addition, disclosed particularly compound also is the particularly preferred compound of the present invention among the embodiment of this specification sheets.
Table-1
-1 (continuing) of table
Figure C0180868700201
-1 (continuing) of table
-1 (continuing) of table
-1 (continuing) of table
Figure C0180868700231
-1 (continuing) of table
Figure C0180868700241
-1 (continuing) of table
Figure C0180868700251
-1 (continuing) of table
Figure C0180868700261
-1 (continuing) of table
Figure C0180868700271
-1 (continuing) of table
Figure C0180868700281
-1 (continuing) of table
Figure C0180868700291
-1 (continuing) of table
Figure C0180868700301
-1 (continuing) of table
Figure C0180868700311
-1 (continuing) of table
Figure C0180868700321
-1 (continuing) of table
Figure C0180868700331
-1 (continuing) of table
Figure C0180868700341
-1 (continuing) of table
Figure C0180868700351
-1 (continuing) of table
Figure C0180868700361
-1 (continuing) of table
Figure C0180868700371
-1 (continuing) of table
Figure C0180868700381
-1 (continuing) of table
Figure C0180868700391
-1 (continuing) of table
Figure C0180868700401
-1 (continuing) of table
Figure C0180868700411
Table-2
Figure C0180868700421
-2 (continuing) of table
Figure C0180868700431
The compound of the present invention of formula (I) expression, there is no particular limitation for its manufacture method, can make according to any method of for example following method.In addition, among the embodiment of this specification sheets, more specifically show the manufacture method of the preferred compound in the The compounds of this invention.The technician of the industry specifies with reference to following general remark and embodiment's, modifies aptly as required and even changes starting raw material, reaction conditions, reaction reagent etc., can make the compound any of the present invention that formula (I) is comprised.
Manufacture method:
Option A:
Figure C0180868700441
Make formula (II) compound (in the formula, Z represents halogen atom or tosyl group [tosylate] or methylsulfonyls [mesylate] etc. such as chlorine atom, bromine atoms or iodine atom, Q ' is-CH 2-,-CO-,-O-or-S-, the definition of X is same as described above) with formula (III) (R 1, R 2, B definition same as described above) shown in nucleophilicity aminoderivative reaction, can obtain corresponding compound (I).Usually, this reaction can be carried out in dimethyl formamide, N-Methyl pyrrolidone, ethanol or acetonitrile isopolarity solvent in the presence of alkali such as triethylamine, sodium bicarbonate or salt of wormwood.
Q ' is-occasion of CO-, by should amino-ketone derivatives (I) reduction, can obtain that A is that hydroxyl, Y are the hydroxy derivatives of hydrogen atom in the formula (I ').Usually, reduction can be used sodium borohydride, in organic solvents such as ethanol, methyl alcohol or tetrahydrofuran (THF), at room temperature carries out.Also can make organometallic reagent reactions such as this amino-ketone derivatives (I) and for example Y-mgBr, coming the middle A of manufacturing formula (I ') is the compound of hydroxyl.
Acyloxy and alkoxy compound can adopt usual method to make from the free hydroxy derivatives.The ortho position alkyl derivative can be made [" Advanced Organic Chemistry " (Advanced Organic Chemistry), J.March.John Wiley﹠amp by the solvolysis of sulphonate [sulfonyl ester] intermediate; Sons, New York, pp.264～317,1985].Also can obtain chirality ether by the solvolysis of chirality sulfonate derivatives such as camphorsulfonic acid ester.Q ' is-during CO-, the oxime of ketone derivatives (I) can adopt " organo-functional group preparation " [(Organic FunctionalGroup Preparation) Vol.III, S.R.Sandler and W.Karo write, Academic Press publishes, London, pp.430～481,1989] in the record the oximate method prepare.
Q ' is-CH in the formula of putting down in writing in the option A (II) 2-or-compound of CO-, can use commercially available product, perhaps the substituent with alkyl or alkyl ketone group carries out halogenation as starting raw material or adopts any method similarly to obtain.Q ' is-O-or-occasion of S-, can use commercially available product, perhaps with the substituent of hydroxyl or thiol group as starting raw material, make itself and Z (CH 2) nZ ' (Z, Z ' expression halogen atom or tosyl group or methylsulfonyl etc.) reacts or adopts any method similarly to synthesize.About synthesizing of benzoisoxazole quinoline derivant and benzisoxa Liu oxazolines derivative, as the one example, can enumerate known references [H.Uno, M.Kurokawa, K.Natsuka, Y.Yamato and H.Nishimura, " chemicals circular " (Chem.Pharm.Bull.), 24 (4), pp.632～643,1976; H.Uno and M.Kurokawa, " chemicals circular " (Chem.Pharm.Bull.), 26 (12), pp.3888～3891,1978] in the method for record.
Option b:
Figure C0180868700451
M is 1 compound in the compound of putting down in writing among the such scheme A as starting raw material (III), can be according to people's such as P.D.Leeson method (" medical chemistry magazine " (J.Med.Chem.), 35,1954～1968,1992), as shown in the above-mentioned option b, make.That is, can be by in the tetracol phenixin equal solvent, with N-bromosuccinimide for example with the compound of formula (IV) (in the formula, R 9The expression alkyl, R 3, R 4, R 5, R 6Definition same as described above) halogenation, obtain the compound (in the formula, Z " be halogen atom) of formula V after, make its compound react to synthesize with formula (VI).
The substituting group P of the compound shown in this scheme is expressed as [T.W.Greene and P.G.M.Wuts, John Wiley﹠amp as " protecting group in the organic synthesis " (Protective Groups in Oranic Synthesis); Sons, New York, 1991] in the amino protecting group put down in writing, this protecting group is easy to be removed, and obtains the piperidine compounds of formula (III).
As other synthesis method of compound shown in the formula (VII), method [I.Takahashi, T.Kawakami, E.Hirano, H.Yokota and H.Kitaj ima, Synlett, 4,353～355,1996 of document record are arranged; S.M.Allin, C.C.Hodkinson and N.Taj, Synlett.8,781～782,1996].
Should illustrate that in the aforesaid method, the compound that is used as starting raw material can be raceme or desirable optically active substance, can make racemization corresponding with them or optically active compound.In addition, also can adopt optical resolution to make desirable optically active body according to method known or commonly used.Formula (I) compound of alkalescence can generate and various mineral acid and organic acid between acid salt, preferred pharmacology on the salt that allows.These salt can pass through at suitable organic solvent, and for example in methyl alcohol, ethanol, Virahol or the ethyl acetate, the basic cpd of handling formula (I) with mineral acid or organic acid easily prepares.
The compound of the present invention of above-mentioned formula (I) expression has the unsymmetrical carbon more than 1 or 2 sometimes, can be used as optical isomer and exists.The mixture of the optical isomer of raceme and pure form and any optical isomer all within the scope of the present invention.Industry technician can adopt known method raceme to be separated into the optical isomer of pure form.In addition, diastereomer or their any mixture based on 2 above unsymmetrical carbons is also contained in the scope of the present invention.The acid salt of the The compounds of this invention of above-mentioned formula (I) expression, the acid salt that allows on the preferred pharmacology, hydrate and arbitrarily solvate be also contained in the scope of the present invention.
As the salt that can form The compounds of this invention, can enumerate for example ammonium salts such as alkaline earth salts such as an alkali metal salts such as organic acid salts such as inorganic acid salts such as hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, phosphoric acid salt, succinate, acetate, glycollate, mesylate, tosylate, sodium salt, sylvite, magnesium salts, calcium salt, ammonium salt, alkylammonium salt etc.In addition, as the solvent of the solvate that can form The compounds of this invention, can enumerate methyl alcohol, ethanol, Virahol, acetone, vinyl acetic monomer etc.Certainly, the form of salt or solvate is not limited to above-mentioned example.
Compound of the present invention has high affinity (in this specification sheets, some compound is being called under the occasion of " sigma ligands ", is being meant that this compound has above-mentioned character) to the σ combining site.Therefore, the various diseases that treats and/or prevents as the mammals that is used to comprise the people, preferred people's the neuroregulation effect of passing through sigma ligands of compound of the present invention and the medicine of symptom are useful.As these diseases, can enumerate for example central nervous system disease, gastrointestinal illness and cardiovascular system diseases.
As central nervous system disease, can enumerate that for example anxiety, melancholia or mood disorders, schizophrenia, lit or narcotic are habit-forming, sharp pain, dyskinesia, cerebrovascular disorder, epilepsy, the dementia that comprises Alzheimer, Parkinsonism, cerebral tumor and attention disappearance hinder.As gastrointestinal illness, can enumerate for example big bowel syndrome of supersensitivity, irritable bowel syndrome, spastic colon, mucous membrane colitis, enterocolitis, diverticulitis and dysentery.In addition, as cardiovascular system diseases, can enumerate for example essential hypertension, arrhythmia and stenocardia.Certainly, the adaption object of medicine of the present invention is not limited to these concrete disease and/or symptoms, goes for treating and/or preventing of in vivo relevant with sigma ligands various diseases and/or symptom.
Compound of the present invention has the effect of good anti-desoxyephedrine (methamphetamine), as particularly the habit-forming medicine that treats and/or prevents usefulness of schizophrenia, lit or narcotic is of great use in above-mentioned disease and the symptom.
As the effective constituent of medicine of the present invention, can use the material of from above-claimed cpd and salt and their hydrate and solvate, selecting more than a kind or 2 kinds.There is no particular limitation for the route of administration of medicine of the present invention, can per os or non-oral administration.As medicine of the present invention, can be with above-mentioned substance intactly to patient's administration, but preferred as the preparation administration that contains the medical composition form of the additive that allows on effective constituent and pharmacology and the technology of pharmaceutics.As the additive that allows on pharmacology and the technology of pharmaceutics, can use for example vehicle, disintegrating agent and even disintegration auxiliary, wedding agent, lubricant, coating-forming agent, pigment, thinner, base, solvating agent and even dissolving auxiliary, isoosmotic pressure agent, pH regulator agent, stabilization agent, propellant and tackiness agent etc.As the example that is suitable for peroral administration preparation, can enumerate for example tablet, capsule, powder, granula subtilis, granule, liquor or syrup etc., as being suitable for para-oral preparation, can enumerate for example injection, some drops, ointment, ointment, transdermic absorbent, eye drops, ear drop, inhalation or suppository etc., but the form of preparation is not limited to this.
Be suitable in the peroral administration preparation,, can use for example vehicle such as glucose, lactose, D-mannitol, starch or crystalline cellulose as additive; Disintegrating agent or disintegration auxiliarys such as carboxymethyl cellulose, starch or calcium carboxymethylcellulose; Wedding agents such as hydroxypropylcellulose, Vltra tears, Polyvinylpyrolidone (PVP) or gelatin; Lubricant such as Magnesium Stearate or talcum; Coating-forming agents such as Vltra tears, white sugar, polyoxyethylene glycol or titanium oxide; Bases such as Vaseline, whiteruss, polyoxyethylene glycol, gelatin, kaolin, glycerine, Purified Water or tristearin.Be suitable for injecting or preparation that drop is used in, can use solvating agent water-baseds such as distilled water for injection, normal saline solution, propylene glycol or that constitute time spent lysotype injection or dissolving auxiliary; Glucose, sodium-chlor, D-mannitol, glycerine or the like osmoticum; Preparation additives such as pH regulator agent such as mineral acid, organic acid, mineral alkali or organic bases.
The dosage of medicine of the present invention should increase and decrease aptly according to conditions such as the purpose of the kind, prevention or the treatment that are suitable for disease, patient's age, body weight, symptoms, in general, the dosage of adult every day, oral administration is about about 0.05～500mg.Usually, can also can be administered once with above-mentioned dosage once a day and even divide administration for several times every several days.
Embodiment
Below, be described more specifically the present invention with embodiment, but scope of the present invention is not limited to these embodiment.
In addition, in the physics value, NMR represents NMR (Nuclear Magnetic Resonance) spectrum, and numeral is for being generally used for representing the δ value of chemical shift, and unit is ppm.Interior mark uses TMS (tetramethylsilane).Should illustrate, the mark in the δ value unquote, s is single line, and d is a doublet, and t is a triplet, and q is a quartet, and m is multiplet, and br is wide absorption peak, and numeral thereafter is a number of hydrogen atoms.
Embodiment 1:2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 1 of table 1)
A) 4-aminomethyl piperidines-1-carboxylic acid tert-butyl ester hydrochloride
As starting raw material, according to " synthesising communication " (SyntheticCommun.), the method for 22 (16), 2357～2360 (1992) middle records is synthesized 4-aminomethyl piperidines-1-carboxylic acid tert-butyl ester with 4-aminomethyl piperidines 5.71g.This compound dissolution in vinyl acetic monomer 80ml, is added 4N hydrochloric acid-vinyl acetic monomer and stirs.Filter and collect the solid of separating out, obtain title compound 10.27g (yield 82%).
236～240 ℃ of fusing points.
1H-NMR(DMSO-d 6)：8.00(3H，s)，3.92(2H，br d，J＝12.6)，2.68(4H，m)，1.77-1.65(3H，m)，1.39(9H，s)，1.02(2H，m)
B) 2-bromomethyl-benzoic acid ethyl ester
With 2-tolyl acid ethyl ester (2.00g 11.9mmol) is dissolved in the tetracol phenixin (60ml), in solution, add N-bromosuccinimide (2.56g, 14.4mmol) and the benzoyl peroxide of catalytic amount, reflux.After 1 hour reaction solution is cooled to room temperature, adds hexane (40ml) then, filter insolubles, filtrate is removed in underpressure distillation, obtains the title compound 3.16g of yellow oil.It is directly used in following reaction without making with extra care.
C) 4-(1-oxygen isoindoline-2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
With the compound (3.00g that obtains among the compound 3.15g, the embodiment 1a that obtain among the embodiment 1b, 12.0mmol) add in the dimethyl formamide (30ml), Yi Bian at room temperature stir, Yi Bian add triethylamine (3.5ml, 25mmol), under uniform temp, stirred 17 hours.In reaction solution, add entry, extract with vinyl acetic monomer-hexane mixed solvent.Organic layer is used dried over mgso with 10% aqueous citric acid solution, water, sodium bicarbonate water, saturated common salt water washing.Filter insolubles, filtrate is removed in underpressure distillation, and the oily matter of acquisition is refining with silica gel column chromatography (vinyl acetic monomer-hexane), obtains the title compound 1.61g (yield 41%) of yellow oil.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.4-7.6(3H，m)，4.41(2H，s)，4.0-4.2(2H，m)，3.4-3.6(2H，m)，2.6-2.8(2H，m)，1.8-2.0(1H，m)，1.5-1.7(4H，m)，1.45(9H，s)
D) 2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
With the compound that obtains among the embodiment 1c (1.61g 4.87mmol) is dissolved in the mixed solvent of methylene dichloride (5ml), ethanol (1ml), at room temperature add 4 equivalent hydrochloric acid vinyl acetic monomer solvents (5ml, 20mmol).Under uniform temp, stirred 1 hour, filter the solid of separating out.The solid that obtains washs with vinyl acetic monomer, and decompression is dry down then, obtains the title compound 726mg (yield 56%) of colorless solid.
1H-NMR(DMSO-d 6)：8.83(1H，brs)，8.53(1H，brs)，7.4-7.7(4H，m)，4.50(2H，s)，3.44(2H，d，J＝7.2)，3.2-3.3(2H，m)，2.7-2.9(2H，m)，1.9-2.1(1H，m)，1.6-1.8(2H，m)，1.3-1.5(2H，m)
E) 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 1d (518mg, 1.94mmol) and 2-chloro-4 '-fluoro acetophenone (358mg 2.07mmol) adds in the dimethyl formamide (12ml), stirring at room temperature on one side, Yi Bian add triethylamine (575 μ l, 4.13mmol).Under uniform temp, stir after 4 hours, in reaction solution, add entry, use ethyl acetate extraction.Dried over sodium sulfate is used in organic layer water, saturated common salt water washing.Filter insolubles, decompression is concentrated filtrate down, obtains orange 0.70g.In the oily matter that obtains, add hexane, make its curing.With its filtration, decompression is dry down, obtains the title compound 551mg (yield 77%) of faint yellow solid.
1H-NMR(CDCl 3)：8.0-8.1(2H，m)，7.85(1H，d＝7.2)，7.4-7.55(3H，m)，7.12(2H，t)，4.41(2H，s)，3.73(2H，s)，3.51(2H，d，J＝7.5)，2.9-3.0(2H，m)，2.1-2.2(2H，m)，1.4-1.9(5H，m)
F) 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(550mg 1.50mmol) is dissolved in the ethanol (2ml), and (2ml 8mmol), stirred 15 minutes under uniform temp at room temperature to add 4 equivalent hydrochloric acid vinyl acetic monomer solvents with the compound that obtains among the embodiment 1e.In reaction solution, add vinyl acetic monomer (10ml), filter the solid of separating out.After the solid that obtains washed with vinyl acetic monomer, decompression was dry down, obtains white powder 364mg.It is used ethanol-vinyl acetic monomer recrystallization, obtain the title compound 246mg (yield 41%) of colorless solid.182～188 ℃ of fusing points.
1H-NMR(DMSO-d 6)：9.93(1H，brs)，8.0-8.2(2H，m)，7.4-7.7(6H，m)，4.9-5.1(2H，m)，4.53(2H，s)，2.9-3.6(6H，m)，1.6-2.2(5H，m)
Embodiment 2:4-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 5 of table 1)
A) 3-bromo-2-tolyl acid ethyl ester
2-tolyl acid ethyl ester (18.3mmol) is splashed in the aluminum chloride (45.7mmol), then splash into Br2 (22.0mmol).After 1 hour, add ice, vinyl acetic monomer in stirring at room in reaction solution, behind the separation organic layer, dried over sodium sulfate is used in water, sodium bicarbonate water, saturated common salt water washing.
Behind the filtering siccative, concentrate, separate 3 kinds of resultants with silica gel column chromatography (hexane-ether).Obtain 3-bromo-2-tolyl acid ethyl ester (yield 14%), 5-bromo-2-tolyl acid ethyl ester (yield 13%), 3,5-two bromo-2-tolyl acid ethyl esters (yield 10%).
3-bromo-2-tolyl acid ethyl ester:
1H-NMR(CDCl 3)：δ7.71(dd，J＝7.9，1.0Hz，1H)，7.69(dd，J＝7.9，1.0Hz，1H)，7.10(t，J＝7.9Hz，1H)，4.37(q，J＝7.0Hz，2H)，2.63(s，3H)，1.40(t，J＝7.0Hz，3H).
5-bromo-2-tolyl acid ethyl ester:
1H-NMR(CDCl 3)：δ8.03(d，J＝2.1Hz，1H)，7.50(dd，J＝8.4，2.1Hz，1H)，7.12(d，J＝8.4Hz，1H)，4.36(q，J＝6.9Hz，2H)，2.54(s，3H)，1.40(t，J＝6.9Hz，3H).
3,5-two bromo-2-tolyl acid ethyl esters:
1H-NMR(CDCl 3)：δ7.85(d，J＝2Hz，1H)，7.84(d，J＝2Hz，1H)，4.37(q，J＝7.0Hz，2H)，2.57(s，3H)，1.40(t，J＝7.0Hz，3H).
B) 4-(4-bromo-1-oxygen isoindoline-2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
Use the 3-bromo-2-tolyl acid ethyl ester that obtains among the embodiment 2a, carry out the operation same, obtain title compound with embodiment 1b, 1c.
1H-NMR(CDCl 3)：δ7.80(d，J＝9Hz，1H)，7.66(d，J＝6Hz，1H)，7.37(dd，J＝9，6Hz，1H)，4.33(s，2H)，4.12(m，2H)，3.54(br d，J＝7Hz，2H)，2.70(br t，J＝12Hz，2H)，1.95(m，1H)，1.66(br d，J＝12Hz，2H)，1.45(s，9H)，1.24(dq，J＝12，4Hz，2H).
C) 4-bromo-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 2b, carry out the operation same, obtain title compound (yield 62%) with embodiment 1d.
1H-NMR(DMSO-d 6)：δ8.92(br s，1H)，8.64(br s，1H)，7.83(d，J＝9Hz，1H)，7.71(d，J＝6Hz，1H)，7.48(dd，J＝9，6Hz，1H)，4.45(s，2H)，3.45(d，J＝12Hz，2H)，3.24(br d，J＝12Hz，2H)，2.79(br q，J＝12Hz，2H)，2.06(m，1H)，1.74(br d，J＝12Hz，2H)，1.37(br q，J＝12Hz，2H).
D) 4-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 2c, carry out the operation same, obtain title compound (yield 57%) with embodiment 1e.
1H-NMR(CDCl 3)：δ8.07(m，2H)，7.79(d，J＝7.8Hz，1H)，7.65(d，J＝7.8Hz，1H)，7.37(t，J＝7.8Hz，1H)，7.11(t，J＝8.6Hz，2H)，4.32(s，2H)，3.72(s，2H)，3.53(d，J＝7.2Hz，2H)，2.96(br d，J＝11.4Hz，2H)，2.16(dt，J＝11.4，2.7Hz，2H)，1.84(m，1H)，1.69(br d，J＝12Hz，2H)，1.48(dq，J＝12，4Hz，2H).
E) 4-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 2d, carry out the operation same, obtain title compound (yield 66%) with embodiment 1f.152～154 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.98(br s，1H)，8.06-8.16(m，2H)，7.84(d，J＝8.1Hz，1H)，7.72(d，J＝7.5Hz，1H)，7.45-7.48(m，3H)，5.04-5.10(m，2H)，4.48(s，2H)，3.00-3.56(m，6H)，2.09(m，1H)，1.58-1.83(m，4H).
Embodiment 3:5-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 4 of table 1)
A) 4-bromo-2-methyl-toluate
With 4-bromo-2-tolyl acid (4.06g 18.5mmol) is dissolved in the methyl alcohol (60ml), add the vitriol oil (1ml) after, reflux 9 hours.Decompression is concentrated solvent down, and after ether (100ml) dilution, dried over mgso is used in water, sodium bicarbonate water, saturated common salt water washing.Filter insolubles, decompression is concentrated filtrate down, obtains the title compound 3.87g (yield 91%) of yellow oil.
1H-NMR(CDCl 3)：7.78(1H，d，J＝8.3)，7.42(1H，d，J＝1.9)，7.38(1H，dd，J＝1.9，8.3)，3.88(3H，s)，2.58(3H，s)
B) 4-bromo-2-bromomethyl-benzoic acid methyl ester
(3.83g 16.7mmol), carries out the operation same with embodiment 1b, obtains title compound 5.70g to use the compound that obtains among the embodiment 3a.It is directly used in following reaction.
C) 4-(5-bromo-1-oxo isoindole is expired-the 2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
Use the compound 5.70g that obtains among the embodiment 3b, carry out the operation same, obtain the title compound 3.04g (yield 44%) of colorless solid with embodiment 1c.
1H-NMR(CDCl 3)：7.69-7.73(1H，m)，7.59-7.62(2H，m)，4.39(2H，s)，4.0-4.2(2H，m)，3.4-3.6(2H，m)，2.5-2.7(2H，m)，1.8-2.0(1H，m)，1.5-1.7(2H，m)，1.45(9H，s)，1.1-1.3(2H，m)
D) 5-bromo-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
(3.03g 7.40mmol), carries out the operation same with embodiment 1d, obtains the title compound 1.86g (yield 73%) of white solid to use the compound that obtains among the embodiment 3c.
1H-NMR(DMSO-d 6)：8.96(1H，brs)，8.68(1H，brs)，7.89(1H，s)，7.69(1H，d，J＝8.2)，7.61(1H，d，J＝8.2)，4.50(2H，s)，3.42(2H，d，J＝7.2)，3.1-3.3(2H，m)，2.6-2.9(2H，m)，1.9-2.1(1H，m)，1.6-1.8(2H，m)，1.2-1.4(2H，m)
E) 5-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(834mg 2.41mmol), carries out the operation same with embodiment 1e, obtains the title compound 727mg (yield 68%) of faint yellow solid to use the compound that obtains among the embodiment 3d.
1H-NMR(CDCl 3)：8.0-8.1(2H，m)，7.68-7.72(1H，m)，7.58-7.62(2H，m)，7.08-7.15(2H，m)，4.38(2H，s)，3.73(2H，s)，3.49(2H，d，J＝7.2)，2.8-3.0(2H，m)，2.0-2.2(2H，m)，1.6-1.9(3H，m)，1.35-1.5(2H，m)
F) 5-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(727mg 1.63mmol), carries out the operation same with embodiment 1f, obtains the title compound 704mg (yield 89%) of colorless solid to use the compound that obtains among the embodiment 3e.205～222 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.91(1H，brs)，8.0-8.2(2H，m)，7.90(1H，s)，7.70(1H，d，J＝8.2)，7.62(1H，d，J＝8.2)，7.4-7.5(2H，m)，5.0-5.2(2H，m)，4.53(2H，s)，3.3-3.6(4H，m)，2.9-3.1(2H，m)，2.0-2.2(1H，m)，1.5-1.9(4H，m)
Embodiment 4:6-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 3 of table 1)
A) 4-(6-bromo-1-oxo isoindole is expired-the 2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
Use the 5-bromo-2-tolyl acid ethyl ester that obtains among the embodiment 2a, carry out the operation same, obtain title compound (yield 52%) with embodiment 1b, 1c.
1H-NMR(CDCl 3)：δ7.98(d，J＝1.8Hz，1H)，7.65(dd，J＝8.0，1.8Hz，1H)，7.32(d，J＝8.0Hz，1H)，4.36(s，2H)，4.10(m，2H)，3.48(m，2H)，2.69(br t，J＝12Hz，2H)，1.93(m，1H)，1.64(br d，J＝12Hz，2H)，1.45(s，9H)，1.24(dq，J＝12.3，4.4Hz，2H).
B) 6-bromo-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 4a, carry out the operation same, obtain title compound (yield 96%) with embodiment 1d.
1H-NMR(DMSO-d 6)：δ8.90(br s，1H)，8.61(br s，1H)，7.78-7.81(m，2H)，7.60(d，J＝8.8Hz，1H)，4.48(s，2H)，3.43(d，J＝7.4Hz，2H)，3.24(br d，J＝12Hz，2H)，2.80(br q，J＝12Hz，2H)，2.01(m，1H)，1.73(br d，J＝12Hz，2H)，1.37(br q，J＝12Hz，2H).
C) 6-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 4b, carry out the operation same, obtain title compound (yield 93%) with embodiment 1e.
1H-NMR(CDCl 3)：δ8.07(m，2H)，7.97(d，J＝1.8Hz，1H)，7.65(dd，J＝8.1，1.8Hz，1H)，7.32(d，J＝8.1Hz，1H)，7.12(t，J＝8.7Hz，2H)，4.36(s，2H)，3.72(s，2H)，3.50(d，J＝6.9Hz，2H)，2.96(br d，J＝12Hz，2H)，2.14(dt，J＝11.6，2.4Hz，2H)，1.82(m，1H)，1.67(br d，J＝12Hz，2H)，1.46(dq，J＝11.7，3.6Hz，2H).
D) 6-bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 4c, carry out the operation same, obtain title compound (yield 72%) with embodiment 1f.187～193 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.99(br s，1H)，8.05-8.16(m，2H)，7.62-7.78(m，2H)，7.60(d，J＝8.6Hz，1H)，7.47(t，J＝8.6Hz，2H)，5.03-5.09(m，2H)，4.51(s，2H)，3.01-3.55(m，6H)，2.03(m，1H)，1.62-1.86(m，4H).
Embodiment 5:4,6-two bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 6 of table 1)
A) 4-(4,6-two bromo-1-oxo isoindoles are expired-the 2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
Use obtain among the embodiment 2a 3,5-two bromo-2-tolyl acid ethyl esters carry out the operation same with embodiment 1b, 1c, obtain title compound (yield 64%).
1H-NMR(CDCl 3)：δ7.93(d，J＝1.5Hz，1H)，7.82(d，J＝1.5Hz，1H)，4.27(s，2H)，4.12(m，2H)，3.51(d，J＝6.7Hz，2H)，2.70(br t，J＝12Hz，2H)，1.94(m，1H)，1.64(br d，J＝12Hz，2H)，1.45(s，9H)，1.25(dq，J＝12，4Hz，2H).
B) 4,6-two bromo-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 5a, carry out the operation same, obtain title compound (yield 100%) with embodiment 1d.
1H-NMR(DMSO-d 6)：δ8.87(br s，1H)，8.60(br s，1H)，4.43(s，2H)，3.44(d，J＝7.5Hz，2H)，3.24(br d，J＝12Hz，2H)，2.79(br q，J＝12Hz，2H)，2.06(m，1H)，1.74(br d，J＝12Hz，2H)，1.36(br q，J＝12Hz，2H).
C) 4,6-two bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 5b, carry out the operation same, obtain title compound (yield 83%) with embodiment 1e.
1H-NMR(CDCl 3)：δ8.07(m，2H)，7.92(d，J＝1.4Hz，1H)，7.81(d，J＝1.4Hz，1H)，7.60(t，J＝8.6Hz，2H)，4.28(s，2H)，3.73(s，2H)，3.51(d，J＝7.3Hz，2H)，2.97(br d，J＝12Hz，2H)，2.16(br t，J＝12Hz，2H)，1.83(m，1H)，1.68(br d，J＝12Hz，2H)，1.47(dq，J＝12，3Hz，2H).
D) 4,6-two bromo-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 5c, carry out the operation same, obtain title compound (yield 77%) with embodiment 1f.186～190 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.03(br s，1H)，8.06-8.16(m，3H)，7.86(s，1H)，7.47(t，J＝8.7Hz，2H)，5.04-5.10(m，2H)，4.46(s，2H)，3.30-3.56(m，6H)，2.08(m，1H)，1.58-1.91(m，4H).
Embodiment 6:4-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 10 of table 1)
A) 3-fluoro-2-tolyl acid ethyl ester
(2.0g 12.98mmol), carries out the operation same with embodiment 3a, obtains the title compound 1.31g of colorless oil to use 3-fluoro-2-tolyl acid.It is directly used in following reaction without making with extra care.
B) 2-brooethyl-3-ethyl fluoro benzoate
Use the compound 1.31g that obtains among the embodiment 6a, carry out the operation same, obtain the title compound 2.01g of faint yellow oily thing with embodiment 1b.It is directly used in following reaction without making with extra care.
C) 4-[(4-fluorine isoindoline-1-ketone)-and the 2-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
Use the compound 1.57g that obtains among the embodiment 6b, carry out the operation same, obtain the title compound 1.68g (yield 63%) of colorless solid with embodiment 1c.
1H-NMR(CDCl 3)：δ7.65(d，1H，J＝7.5Hz)，7.49-7.43(ddd，1H，J＝7.8，7.8，4.8Hz)，7.22(dd，1H，J＝8.6，8.5Hz)，4.45(s，2H)，4.11(brd，2H，J＝11.7Hz)，3.50(br d，2H，J＝6.3Hz)，2.70(br dd，2H，J＝12.6，6.3Hz)，1.98-1.91(m，1H)，1.67-1.62(m，2H)，1.45(s，9H)，1.35-1.19(m，2H).
D) 4-fluoro-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
(1.68g 4.82mmol), carries out the operation same with embodiment 1d, obtains the title compound 1.27g (yield 93%) of colorless solid to use the compound that obtains among the embodiment 6c.
1H-NMR(DMSO-d 6)：δ8.91(br s，1H)，8.65(br s，1H)，7.60-7.42(m，3H)，4.60(s，2H)，3.44(d，2H，J＝7.5Hz)，3.24(br d，2H，J＝12.6Hz)，2.79(brdd，2H，J＝23.3，12.2Hz)，2.08-1.99(m，1H)，1.74(br d，2H，J＝12.3Hz)，1.45-1.31(m，2H).
E) 4-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(1.27g 4.46mmol), carries out the operation same with embodiment 1e, obtains filbert solid title compound 1.52g (yield 89%) to use the compound that obtains among the embodiment 6d.
1H-NMR(CDCl 3)：δ8.10-8.05(m，2H)，7.65(d，1H，J＝7.3Hz)，7.46-7.44(m，1H)，7.21(dd，2H，J＝8.8，8.8Hz)，7.11(dd，2H，J＝7.6，7.6Hz)，4.45(s，2H)，3.71(s，2H)，3.52(d，2H，J＝7.2Hz)，2.96(br d，2H，J＝11.6Hz)，2.19-2.08(m，2H)，1.71-1.67(m，2H)，1.54-1.46(m，2H).
F) 4-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(500mg 1.30mmol), carries out the operation same with embodiment 1f, obtains the title compound 484mg (yield 89%) of colorless solid to use the compound that obtains among the embodiment 6e.177～196 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.92(br s，1H)，8.16-8.06(m，2H)，7.59-7.44(m，5H)，5.04-5.01(m，2H)，4.63(s，2H)，3.56-3.46(m，4H)，3.02(br d，2H，J＝10.8Hz)，2.09-2.06(m，1H)，1.91-1.62(m，4H).
Embodiment 7:6-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 8 of table 1)
A) 5-fluoro-2-methyl-toluate
(900mg 5.78mmol), carries out the operation same with embodiment 3a, obtains the title compound 1.01g of colorless oil to use 5-fluoro-2-tolyl acid.It is directly used in following reaction without making with extra care.
B) 2-brooethyl-5-fluorophenyl carbamate
Use the compound 957mg that obtains among the embodiment 7a, carry out the operation same, obtain title compound 1.57g with embodiment 1b.It is directly used in following reaction without making with extra care.
C) 4-(6-fluoro-1-oxo isoindole is expired-the 2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
Use the compound 1.57g that obtains among the embodiment 7b, carry out the operation same, obtain the title compound 1.13g (yield 57%) of colorless solid with embodiment 1c.
1H-NMR(CDCl 3)：7.50-7.54(1H，m)，7.38-7.43(1H，m)，7.20-7.28(1H，m)，4.38(2H，s)，4.0-4.2(2H，m)，3.4-3.6(2H，m)，2.6-2.8(2H，m)，1.8-2.0(1H，m)，1.5-1.7(2H，m)，1.45(9H，s)，1.1-1.3(2H，m)
D) 6-fluoro-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
(1.09g 3.13mmol), carries out the operation same with embodiment 1d, obtains the title compound 722mg (yield 81%) of colorless solid to use the compound that obtains among the embodiment 7c.
1H-NMR(DMSO-d 6)：8.73(1H，brs)，8.46(1H，brs)，7.63-7.69(1H，m)，7.43-7.49(2H，m)，4.48(2H，s)，3.44(2H，d，J＝7.3)，3.1-3.3(2H，m)，2.7-2.9(2H，m)，1.9-2.1(1H，m)，1.6-1.8(2H，m)，1.2-1.4(2H，m)
E) 6-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(721mg 2.53mmol), carries out the operation same with embodiment 1e, obtains the title compound 762mg (yield 78%) of faint yellow solid to use the compound that obtains among the embodiment 7d.
1H-NMR(CDCl 3)：8.04-8.10(2H，m)，7.49-7.53(1H，m)，7.37-7.41(1H，m)，7.22-7.26(1H，m)，7.08-7.15(2H，m)，4.38(2H，s)，3.73(2H，s)，3.50(2H，d，J＝7.3)，2.9-3.0(2H，m)，2.0-2.2(2H，m)，1.7-1.9(1H，m)，1.5-1.7(2H，m)，1.3-1.5(2H，m)
F) 6-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(762mg 1.98mmol), carries out the operation same with embodiment 1f, obtains the title compound 762mg (yield 91%) of colorless solid to use the compound that obtains among the embodiment 7e.193～205 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.96(1H，brs)，8.0-8.2(2H，m)，7.64-7.70(1H，m)，7.3-7.5(4H，m)，5.0-5.2(2H，m)，4.52(2H，s)，3.4-3.6(4H，m)，3.9-4.1(2H，m)，1.9-2.1(1H，m)，1.5-1.9(4H，m)
Embodiment 8:5-chloro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 13 of table 1)
A) 4-chloro-2-tolyl acid ethyl ester
(300mg 1.76mmol), carries out the operation same with embodiment 3a, obtains the title compound 347mg of colorless solid to use 4-chloro-2-tolyl acid.It is directly used in following reaction without making with extra care.
B) 2-brooethyl-4-chloro-benzoic acid ethyl ester
Use the compound 347mg that obtains among the embodiment 8a, carry out the operation same, obtain the title compound 494mg of filbert oily thing with embodiment 1b.It is directly used in following reaction without making with extra care.
C) 4-[(5-chlorine isoindoline-1-ketone)-and the 2-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
Use the compound 490mg that obtains among the embodiment 8b, carry out the operation same, obtain filbert solid title compound 375mg (yield 58%) with embodiment 1c.
1H-NMR(CDCl 3)：δ7.77(d，1H，J＝8.7Hz)，7.48-7.44(m，2H)，4.39(s，2H)，4.11(br s，2H)，3.49(br s，2H)，2.69(br dd，2H，J＝12.2，12.2Hz)，1.97-1.89(m，1H)，1.66-1.62(m，2H)，1.45(s，9H)，1.31-1.18(m，2H).
D) 5-chloro-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
(370mg 1.01mmol), carries out the operation same with embodiment 1d, obtains the title compound 211mg (quantitative yield) of colorless solid to use the compound that obtains among the embodiment 8c.
1H-NMR(DMSO-d 6)：δ9.08(br s，1H)，8.81(br s，1H)，7.80(s，1H)，7.74(d，1H，J＝8.0Hz)，7.60(dd，1H，J＝8.1，1.6Hz)，4.56(s，2H)，3.48(d，2H，J＝7.4Hz)，3.29(br d，2H，J＝12.6Hz)，-2.85(br dd，2H，J＝23.0，12.0Hz)，2.10-2.02(m，1H)，1.78(br d，2H，J＝12.8Hz)，1.51-1.37(m，2H).
E) 5-chloro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(205mg 0.68mmol), carries out the operation same with embodiment 1e, obtains the title compound 213mg (yield 78%) of white solid to use the compound that obtains among the embodiment 8d.
1H-NMR(CDCl 3)：δ8.07(dd，2H，J＝8.9，5.6Hz)，7.76(d，1H，J＝9.0Hz)，7.44(d，2H，J＝8.1Hz)，7.12(dd，2H，J＝8.7，8.7Hz)，4.39(s，2H)，3.73(s，2H)，3.49(d，2H，J＝7.2Hz)，2.96(br d，2H，J＝11.4Hz)，2.19-2.11(m，2H)，1.84-1.77(m，1H)，1.68(br d，2H，J＝12.6Hz)，1.54-1.45(m，2H).
F) 5-chloro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(213mg 0.53mmol), carries out the operation same with embodiment 1f, obtains the title compound 155mg (yield 48%) of colorless solid to use the compound that obtains among the embodiment 8e.209～221 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.94(br s，1H)，8.19-8.06(m，2H)，7.76(s，1H)，7.69(d，1H，J＝8.1Hz)，7.65(d，1H，J＝9.3Hz)，7.48(dd，2H，J＝8.7，8.7Hz)，5.10-5.03(m，2H)，4.54(s，2H)，3.55-3.40(m，4H)，3.08-3.00(m，2H)，2.09-1.99(m，1H)，1.86-1.61(m，4H).
Embodiment 9:5-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 17 of table 1)
A) 4-methoxyl group-2-methyl-toluate
4-bromo-2-methyl-toluate (19.0mmol) is dissolved in dimethyl formamide
(2.7mL), in the methyl alcohol (1.1mL), be heated to 80 ℃ after, add CuBr (1.09mmol).After the heated and stirred 2 hours, be cooled to room temperature, add ether 25mL, filter, after filtrate water * 4, sodium bicarbonate water, the saturated common salt water washing, use dried over sodium sulfate, the filtering siccative after concentrating, obtains title compound.
1H-NMR(CDCl 3)：δ7.93(d，J＝9.3Hz，1H)，6.72-6.76(m，2H)，3.86(s，3H)，3.84(s，3H)，2.60(s，3H).
B) 4-(5-methoxyl group-1-oxo isoindole is expired-the 2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
Use the compound that obtains among the embodiment 9a, carry out the operation same, obtain title compound (yield 40%) with embodiment 1b, 1c.
1H-NMR(CDCl 3)：δ7.75(d，J＝8.4Hz，1H)，6.99(dd，J＝8.4，2.1Hz，1H)，6.93(d，J＝2.1Hz，1H)，4.35(s，2H)，4.11(m，2H)，3.87(s，3H)，3.47(m，2H)，2.69(br t，J＝12Hz，2H)，1.93(m，1H)，1.65(br d，J＝12Hz，2H)，1.45(s，9H)，1.24(dq，J＝12，4Hz，2H).
C) 5-methoxyl group-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 9b, carry out the operation same, obtain title compound (yield 100%) with embodiment 1d.
1H-NMR(DMSO-d 6)：δ9.13(br s，1H)，8.86(br s，1H)，7.57(d，J＝8.4Hz，1H)，7.15(d，J＝2.2Hz，1H)，7.02(dd，J＝8.6，2.2Hz，1H)，4.43(s，2H)，3.83(s，3H)，3.39(d，J＝7.4Hz，2H)，3.22(br d，J＝12Hz，2H)，2.78(br q，J＝12Hz，2H)，1.98(m，1H)，1.71(br d，J＝12Hz，2H)，1.43(br q，J＝12Hz，2H).
D) 5-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 9c, carry out the operation same, obtain title compound (yield 84%) with embodiment 1e.
1H-NMR(CDCl 3)：δ8.08(m，2H)，7.75(d，J＝7.8Hz，1H)，7.11(t，J＝8.4Hz，2H)，6.98(dd，J＝8.4，2.4Hz，1H)，6.77(d，J＝2.4Hz，1H)，4.34(s，2H)，3.87(s，3H)，3.71(s，2H)，3.47(d，J＝7.2Hz，2H)，2.95(br d，J＝12Hz，2H)，2.15(dt，J＝11.7，2.4Hz，2H)，1.80(m，1H)，1.67(br d，J＝12Hz，2H)，1.46(dq，J＝12，4Hz，2H).
E) 5-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 9d, carry out the operation same, obtain title compound (yield 65%) with embodiment 1f.205～214 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.07(br s，1H)，8.06-8.16(m，2H)，7.59(d，J＝8.4Hz，1H)，7.47(t，J＝8.4Hz，2H)，7.17(s，1H)，7.03(d，J＝8.4Hz，1H)，5.06-5.12(m，2H)，4.47(s，2H)，3.84(s，3H)，3.02-3.52(m，6H)，2.01(m，1H)，1.63-1.84(m，4H).
Embodiment 10:5-cyano group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 21 of table 1)
A) 4-cyano group-2-methyl-toluate
4-bromo-2-phenylformic acid (1 7.5 mmol) is dissolved among N-N-methyl-2-2-pyrrolidone N-24 mL, adds CuCN (21.0 mmol), be heated to 180 ℃.5 hours postcooling add entry 40mL to room temperature, filter.Remaining solid acetone extract after concentrating, obtains title compound (yield 45%).
1H-NMR(CDCl 3)：δ 7.97(d，J＝8.6 Hz，1H)，7.55(s，1H)，7.54(d，J＝8.6Hz，1H)，3.93(s，3H)，2.62(s，3H).
B) 4-(5-cyano group-1-oxo isoindole is expired-the 2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
Use the compound that obtains among the embodiment 10a, carry out the operation same, obtain title compound (yield 40%) with embodiment 1b, 1c.
1H-NMR(CDCl 3)：δ7.96(d，J＝7.5 Hz，1H)，7.78(d，J＝7.5 Hz，1H)，7.76(s，1H)，4.48(s，2H)，4.11(m，2H)，3.53(m，2H)，2.69(br t，J＝12 Hz，2H)，1.95(m，1H)，1.64(br d，J＝12 Hz，2H)，1.45(s，9H)，1.26(dq，J＝12，4Hz，2H).
C) 5-cyano group-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 10b, carry out the operation same, obtain title compound (yield 100%) with embodiment 1d.
1H-NMR(DMSO-d 6)：δ 9.06(br s，1 H)，8.80(br s，1H)，8.16(s，1H)，7.95(d，J＝7.4Hz，1H)，7.84(d，J＝7.4 Hz，1H)，4.57(s，2H)，3.45(d，J＝7.3 Hz，2H)，3.22(br d，J＝12 Hz，2H)，2.78(br q，J＝1 2 Hz，2H)，2.02(m，1H)，1.73(br d，J＝12 Hz，2H)，1.39(br q，J＝12 Hz，2H).
D) 5-cyano group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 10c, carry out the operation same, obtain title compound (yield 79%) with embodiment 1e.
1H-NMR(CDCl 3)：δ8.07(m，2H)，7.95(d，J＝7.8 Hz，1H)，7.77(d，J＝7.8 Hz，1H)，7.76(s，1H)，7.12(t，J＝8.4 Hz，2H)，4.48(s，2H)，3.74(s，2H)，3.54(d，J＝7.2 Hz，2H)，2.97(br d，J＝12 Hz，2H)，2.1 5(dt，J＝11.4，2.1Hz，2H)，1.84(m，1 H)，1.66(br d，J＝12 Hz，2H)，1.48(dq，J＝12，4 Hz，2H).
E) 5-cyano group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 10d, carry out the operation same, obtain title compound (yield 85%) with embodiment 1f.212～217 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.00(br s，1H)，8.18(s，1H)，8.06-8.14(m，2H)，7.97(d，J ＝8Hz，1H)，7.86(d，J＝8Hz，1H)，7.48(t，J＝8.8Hz，2H)，5.06-5.12(m，2H)，4.61(s，2H)，3.01-3.61(m，6H)，2.06(m，1H)，1.59-1.87(m，4H).
Embodiment 11:4-nitro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 25 of table 1)
A) 2-methyl-3-nitro methyl benzoate
(3.0g 16.56mmol), carries out the operation same with embodiment 3a, obtains the title compound 1.74g of colorless solid to use 2-methyl-3-nitro phenylformic acid.It is directly used in following reaction without making with extra care.
B) 2-brooethyl-3-nitrobenzoic acid methyl esters
Use the compound 1.00g that obtains among the embodiment 11a, carry out the operation same, obtain the title compound 1.43g of faint yellow oily thing with embodiment 1b.It is directly used in following reaction without making with extra care.
C) 4-[(4-nitro isoindoline-1-ketone)-and the 2-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
Use the compound 783mg that obtains among the embodiment 11b, carry out the operation same, obtain filbert solid title compound 590mg (yield 56%) with embodiment 1c.
1H-NMR(CDCl 3)：δ8.40(dd，1H，J＝8.2，0.9Hz)，8.19(d，1H，J＝7.6Hz)，7.71(dd，1H，J＝7.9，7.9Hz)，4.88(s，2H)，4.11(br s，2H)，3.57(br d，2H，J＝7.2Hz)，2.71(br dd，2H，J＝12.9，12.9Hz)，2.04-1.96(m，1H)，1.69-1.58(m，2H)，1.45(s，9H)，1.35-1.21(m，2H).
D) 4-nitro-2 (piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
(590mg 1.57mmol), carries out the operation same with embodiment 1d, obtains the title compound 454mg (yield 93%) of colorless solid to use the compound that obtains among the embodiment 11c.
1H-NMR(DMSO-d 6)：δ8.96(br s，1H)，8.71(br s，1H)，8.45(d，1H，J＝8.4Hz)，8.13(d，1H，J＝7.5Hz)，7.82(dd，1H，J＝7.8，7.8Hz)，4.94(s，2H)，3.50(d，2H，J＝7.5Hz)，3.25(br d，2H，J＝12.3Hz)，2.77(brdd，2H，J＝23.1，11.7Hz)，2.13-2.06(m，1H)，1.76(br d，2H，J＝12.6Hz)，1.47-1.33(m，2H).
E) 4-nitro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(454mg 1.46mmol), carries out the operation same with embodiment 1e, obtains the title compound 344mg (yield 57%) of faint yellow solid to use the compound that obtains among the embodiment 11d.
1H-NMR(CDCl 3)：δ8.40(d，1H，J＝8.2Hz)，8.18(d，1H，J＝7.4Hz)，8.10-8.05(m，2H)，7.70(dd，1H，J＝7.8，7.8Hz)，7.09(dd，2H，J＝8.6，8.6Hz)，4.88(s，2H)，3.72(s，2H)，3.57(d，2H，J＝7.2Hz)，2.97(br d，2H，J＝11.5Hz)，2.21-2.12(m，2H)，1.88-1.83(m，1H)，1.71(br s，2H)，1.56-1.47(m，2H).
F) 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-4-nitro isoindoline-1-keto hydrochloride
(320mg 0.78mmol), carries out the operation same with embodiment 1f, obtains the title compound 262mg (yield 75%) of colorless solid to use the compound that obtains among the embodiment 11e.177～181 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.90(br s，1H)，8.46(d，1H，J＝8.4Hz)，8.16-8.09(m，3H)，7.83(dd，1H，J＝7.8，7.8Hz)，7.48(dd，2H，J＝8.7，8.7Hz)，4.97(s，4H)，3.53(br s，4H)，3.02(br s，2H)，2.12(br s，1H)，1.83-1.61(m，4H).
Embodiment 12:6-nitro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 23 of table 1)
A) 2-methyl-5-nitro methyl benzoate
(2.0g 11.04mmol), carries out the operation same with embodiment 3a, obtains the title compound 2.14g of colorless solid to use 2-methyl-5-nitro phenylformic acid.It is directly used in following reaction without making with extra care.
B) 2-brooethyl-5-nitrobenzoic acid methyl esters
Use the compound 2.14g that obtains among the embodiment 12a, carry out the operation same, obtain the title compound 3.22g of filbert oily thing with embodiment 1b.It is directly used in following reaction without making with extra care.
C) 4-[(6-nitro isoindoline-1-ketone)-and the 2-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
Use the compound 3.22g that obtains among the embodiment 12b, carry out the operation same, obtain filbert solid title compound 864mg (yield 21%) with embodiment 1c.
1H-NMR(CDCl 3)：δ8.68(d，1H，J＝2.1Hz)，8.43(dd，1H，J＝8.4，1.8Hz)，7.62(d，1H，J＝8.1Hz)，4.53(s，2H)，4.11(br s，2H)，3.53(br s，2H)，2.70(brdd，2H，J＝12.0，12.0Hz)，2.00-1.92(m，1H)，1.68-1.64(m，2H)，1.45(s，9H)，1.33-1.20(m，2H).
D) 6-nitro-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
(860mg 2.29mmol), carries out the operation same with embodiment 1d, obtains the title compound 732mg (quantitative yield) of colorless solid to use the compound that obtains among the embodiment 12c.
1H-NMR(DMSO-d 6)：δ8.93(br s，1H)，8.67(br s，1H)，8.47(dd，1H，J＝8.3，2.3Hz)，8.35(d，1H，J＝2.1Hz)，7.92(d，1H，J＝8.4Hz)，4.67(s，2H)，3.46(br s，2H)，3.25(br d，2H，J＝12.3Hz)，2.80(brdd，2H，J＝23.1，12.0Hz)，2.07-2.00(m，1H)，1.75(br d，2H，J＝12.3Hz)，1.46-1.34(m，2H).
E) 6-nitro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(725mg 2.33mmol), carries out the operation same with embodiment 1e, obtains the title compound 637mg (yield 67%) of faint yellow solid to use the compound that obtains among the embodiment 12d.
1H-NMR(CDCl 3)：δ8.68(d，1H，J＝2.1Hz)，8.43(dd，1H，J＝8.4，2.1Hz)，8.09-8.02(m，2H)，7.63(d，1H，J＝8.4Hz)，7.16-7.08(m，2H)，4.54(s，2H)，3.74(s，2H)，3.55(d，2H，J＝7.2Hz)，2.98(br d，2H，J＝9.9Hz)，2.20-2.19(m，2H)，1.87-1.81(m，1H)，1.70(br d，2H，J＝12.9Hz)，1.56-1.47(m，2H).
F) 6-nitro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
(287mg 0.70mmol) is dissolved in methylene dichloride (3ml) and the acetone (3ml), and (41mg 0.35mmol), stirred 3 hours at room temperature to add fumaric acid with the compound that obtains among the embodiment 12e.Filter and collect the solid of separating out, obtain the title compound 148mg (yield 40%) of colorless solid.195～206 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ8.46(dd，1H，J＝8.3，2.3Hz)，8.34(d，1H，J＝2.4Hz)，8.11-8.07(m，2H)，7.88(d，1H，J＝8.4Hz)，7.38-7.32(m，2H)，6.61(s，2H)，4.66(s，2H)，3.86(s，2H)，3.44(d，2H，J＝7.5Hz)，2.90(br d，2H，J＝11.4Hz)，2.16(br t，2H，J＝10.8Hz)，1.79-1.74(m，1H)，1.59(br d，2H，J＝11.7Hz)，1.30-1.19(m，2H).
Embodiment 13:2-[[1-(2-phenyl-2-oxoethyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 26 of table 1)
A) 2-[[1-(2-phenyl-2-oxoethyl) piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 1d (400mg, 1.50mmol), the 2-bromoacetophenone (299mg, 1.50mmol) and triethylamine (0.46ml, dimethyl formamide solution 3.30mmol) (3ml) at room temperature stirred 3 hours.In reaction solution, add entry (10ml), after at room temperature stirring, filter and collect the crystallization of separating out, wash with water, obtain title compound 319mg (yield 61%).
1H-NMR(CDCl 3)：8.01(d，2H)，7.84(d，1H)，7.56-7.42(m，6H)，4.41(s，2H)，3.79(s，1H)，3.51(d，2H)，3.00(br d，2H)，2.16(dt，2H)，1.82(m，1H)，1.70(m，2H)，1.52(dt，2H).
B) 2-[[1-(2-phenyl-2-oxoethyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
The compound 319mg that obtains among the embodiment 13a is dissolved in ethanol-vinyl acetic monomer, adds 4N hydrochloric acid/vinyl acetic monomer solution, filter and collect the crystallization of separating out, obtain the title compound 299mg (yield 85%) of white solid.190～197 ℃ of fusing points.
1H-NMR(DMSO-d 6)：9.91(br s，1H)，8.03(m，2H)，7.77(m，1H)，7.65(m，1H)，7.49(m，1H)，5.06(m，2H)，4.54(s，2H)，3.48(m，2H)，3.03(m，2H)，2.04(m，1H)，1.99-1.61(m，4H).
Embodiment 14:2-[[1-[2-(4-chloro-phenyl-)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 51 of table 1)
A) 2-[[1-[2-(4-chloro-phenyl-)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 1d (400mg, 1.50mmol), 2-bromo-4 '-chloro-acetophenone (350mg, 1.50mmol) and triethylamine (0.46ml, dimethyl formamide solution 3.30mmol) (3ml) at room temperature stirred 3 hours.After in reaction solution, adding entry, use ethyl acetate extraction, wash 4 times with water after, use dried over sodium sulfate.Distillation is carried out crystallization with vinyl acetic monomer-hexane after removing and desolvating, and obtains title compound 318mg (yield 55%).
1H-NMR(CDCl 3)：7.99(d，2H)，7.84(d，2H)，7.56-7.40(m，5H)，4.41(s，2H)，3.73(s，2H)，3.51(d，1H)，2.95(br d，2H)，2.15(dt，2H)，1.82(m，1H)，1.70(m，2H)，1.50(dt，2H).
B) 2-[[1-[2-(4-chloro-phenyl-)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
The compound 318mg that obtains among the embodiment 14a is dissolved in ethanol-vinyl acetic monomer, adds 4N hydrochloric acid/vinyl acetic monomer solution, filter and collect the crystallization of separating out, obtain the title compound 268mg (yield 77%) of white solid.188～196 ℃ of fusing points.
1H-NMR(DMSO-d 6)：9.97(br s，1H)，8.00(m，2H)，7.68(m，3H)，7.57(m，2H)，7.47(m，1H)，5.03(m，2H)，4.51(s，2H)，3.54-2.95(m，6H)，1.97(m，1H)，1.80-1.60(m，4H).
Embodiment 15:2-[[1-[2-(4-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 64 of table 1)
A) 2-[[1-[2-(4-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 1d (400mg, 1.50mmol), 2-bromo-4 '-methoxyacetophenone (344mg, 1.50mmol) and triethylamine (0.46ml, dimethyl formamide solution 3.30mmol) (3ml) at room temperature stirred 3 hours.In reaction solution, add entry (10ml), after at room temperature stirring, filter and collect the crystallization of separating out, wash with water, obtain title compound 537mg (yield 95%).
1H-NMR(CDCl 3)：8.02(d，2H)，7.85(d，1H)，7.53-7.42(m，3H)，6.91(d，2H)，4.41(s，2H)，3.87(s，3H)，3.73(s，2H)，3.51(d，2H)，2.98(br d，2H)，2.15(dt，2H)，1.81(m，1H)，1.70(m，2H)，1.51(dt，2H).
B) 2-[[1-[2-(4-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
The compound 537mg that obtains among the embodiment 15a is dissolved in ethanol-vinyl acetic monomer, adds 4N hydrochloric acid/vinyl acetic monomer solution, filter and collect the crystallization of separating out, obtain the title compound 444mg (yield 75%) of white solid.163～168 ℃ of fusing points.
1H-NMR(DMSO-d 6)：9.85(br s，1H)，7.95(m，2H)，7.67(d，1H)，7.59(d，2H)，7.47(m，1H)，7.12(d，2H)，4.95(m，2H)，4.51(s，2H)，3.86(s，3H)，3.45(m，4H)，2.99(m，2H)，2.01(m，1H)，1.65(m，4H).
Embodiment 16:(R, S)-2-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 77 of table 1)
A) (R, S)-2-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 1f (403mg 1.0mmol) handles with methylene dichloride and 1N aqueous sodium hydroxide solution, dichloromethane layer with dried over sodium sulfate after, distillation removes and desolvates.The residue that obtains is made ethanolic soln (15ml), and (30mg 0.79mmol), at room temperature stirred 2 hours to add sodium borohydride.After distillation removes and desolvates, add entry it is suspended, filter and collect the crystallization that obtains, obtain the title compound 331mg (yield 90%) of white solid.
1H-NMR(CDCl 3)：7.86(d，1H)，7.55-7.43(m，3H)，7.32(m，2H)，7.02(m，2H)，4.69(m，1H)，4.42(s，2H)，3.53(d，2H)，3.15(m，1H)，2.82(m，1H)，2.49-2.00(m，4H)，1.84(m，1H)，1.70(m，2H)，1.40(m，2H).
B) (R, S)-2-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
The compound 331mg that obtains among the embodiment 16a is dissolved in ethanol-vinyl acetic monomer, adds 4N hydrochloric acid/vinyl acetic monomer solution, filter and collect the crystallization of separating out, obtain the title compound 347mg (yield 95%) of white solid.223～228 ℃ of fusing points.
1H-NMR(DMSO-d 6)：9.82(br s，1H)，7.68(d，1H)，7.61(d，2H)，7.48(m，3H)，7.22(m，2H)，6.26(m，1H)，5.15(m，1H)，4.52(s，2H)，3.63(m，2H)，3.45(d，2H)，3.18(m，2H)，2.95(m，2H)，1.99(m，1H)，1.86-1.57(m，4H).
Embodiment 17:(R, S)-5-bromo-2-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 79 of table 1) a) (R, S)-5-bromo-2-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(678mg 1.52mmol), carries out the operation same with embodiment 16a, obtains the title compound 677mg (yield 99%) of colorless solid to use the compound that obtains among the embodiment 3e.
1H-NMR(CDCl 3)：7.70-7.74(1H，m)，7.60-7.63(2H，m)，7.31-7.36(2H，m)，6.99-7.06(2H，m)，4.69(1H，dd，J＝3.6，10.2)，4.40(2H，s)，3.51(2H，d，J＝6.9)，3.1-3.2(1H，m)，2.7-2.8(1H，m)，2.30-2.51(2H，m)，2.2-2.3(1H，m)，2.0-2.1(1H，m)，1.3-1.9(5H，m)
B) (R, S)-5-bromo-2-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(313mg 0.700mmol), carries out the operation same with embodiment 1f, obtains the title compound 317mg (yield 94%) of colorless solid to use the compound that obtains among the embodiment 17a.230～240 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.81(1H，brs)，7.90(1H，d，J＝0.9)，7.70(1H，dd，J＝0.9，8.0)，7.62(1H，d，J＝8.0)，7.43-7.53(2H，m)，7.20-7.26(2H，m)，6.29-6.31(1H，m)，5.0-5.2(1H，m)，4.52(2H，s)，3.5-3.7(2H，m)，2.8-3.5(4H，m)，1.5-2.2(5H，m)
Embodiment 18:2-[[1-[2-(4-fluorophenyl)-2-(Z)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the Z body of the compound 90 of table 1)
A) 2-[[1-[2-(4-fluorophenyl)-2-(E, Z)-the oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(496mg 1.35mmol) is dissolved in ethanol (10ml), pyridine (10ml) mixed solvent, and (255mg 3.67mmol), stirred 5 days under uniform temp at room temperature to add hydroxylamine hydrochloride with the compound that obtains among the embodiment 1e.Use the vinyl acetic monomer dilute reaction solution, after sodium bicarbonate water, saturated common salt water washing, use dried over sodium sulfate.After filtering insolubles, underpressure distillation removes and desolvates, and the solid that obtains is refining with silica gel column chromatography (methyl alcohol-methylene dichloride), obtains the title compound 295mg (yield 57%) and the E body 216mg (yield 42%) of colorless solid.
(Z body)
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.4)，7.42-7.64(5H，m)，7.01-7.07(2H，m)，4.41(2H，s)，3.74(2H，s)，3.52(2H，d，J＝7.4)，3.0-3.1(2H，m)，2.13-2.22(2H，m)，1.8-2.0(1H，m)，1.7-1.8(2H，m)，1.3-1.5(2H，m)
(E body)
1H-NMR(CDCl 3)：7.84(1H，d，J＝6.9)，7.61-7.67(2H，m)，7.41-7.54(3H，m)，7.05-7.12(2H，m)，4.38(2H，s)，3.48(2H，d，J＝7.2)，3.31(2H，s)，2.8-3.0(2H，m)，1.9-2.05(2H，m)，1.5-1.8(3H，m)，1.3-1.4(2H，m)
B) 2-[[1-[2-(4-fluorophenyl)-2-(Z)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
(289mg 0.756mmol), carries out the operation same with embodiment 36c, obtains the title compound 320mg (yield 85%) of colorless solid to use the Z body compound that obtains among the embodiment 18a.178～180 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.76-7.81(2H，m)，7.4-7.7(4H，m)，7.16-7.23(2H，m)，6.62(2H，s，fumaric acid)，4.45(2H，s)，3.61(2H，s)，3.2-3.4(2H，m)，2.7-2.8(2H，m)，1.9-2.1(2H，m)，1.6-1.8(1H，m)，1.4-1.6(2H，m)，1.0-1.2(2H，m)
Embodiment 19:2-[[1-[2-(4-fluorophenyl)-2-(E)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the E body of the compound 90 of table 1)
(214mg 0.560mmol), carries out the operation same with embodiment 36c, obtains the title compound 225mg (yield 81%) of colorless solid to use the E body compound that obtains among the embodiment 18a.186～188 ℃ of fusing points
1H-NMR(DMSO-d 6)：11.03(1H，brs，OH)，7.4-7.7(6H，m)，7.19-7.25(2H，m)，6.62(2H，s，fumaric acid)，4.46(2H，s)，3.2-3.4(2H，m)，2.8-2.9(2H，m)，1.9-2.05(2H，m)，1.6-1.8(1H，m)，1.4-1.6(2H，m)，1.0-1.2(2H，m)
Embodiment 20:2-[[1-[2-(2,4 difluorobenzene base)-2-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 116 of table 1)
A) 2-chloro-2 ', 4 '-the difluoro acetophenone oxime
With 2-chloro-2 ', 4 '-(3.09g 16.2mmol) is dissolved in the ethanol (30ml) difluoro acetophenone.Ice-cold add in turn down hydroxylamine hydrochloride (1.23g, 17.7mmol), (1.45g 17.7mmol), is warming up to room temperature to sodium-acetate, stirs 20 hours.Reaction solvent is removed in decompression distillation down, after the vinyl acetic monomer dilution, with sodium bicarbonate water, saturated common salt water washing, uses dried over mgso.After filtering insolubles, underpressure distillation removes and desolvates, and with hexane dry-cleaning [け ん washes ] after drying, obtains the title compound 2.29g (yield 69%) of colorless solid.
1H-NMR(CDCl 3)：8.74(1H，s)，7.48-7.56(1H，m)，6.85-6.99(2H，m)，4.63(2H，s)
B) 2-[[1-[2-(2,4 difluorobenzene base)-2-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 20a (710mg, 3.45mmol), (880mg 3.30mmol), carries out the operation same with embodiment 1e, obtains the title compound 1.38g (yield 100%) of colorless solid for the compound that obtains among the embodiment 1d.
1H-NMR(CDCl 3)：8.3(1H，brs)，7.84(1H，d，J＝7.5)，7.41-7.53(3H，m)，7.25-7.31(1H，m)，6.81-6.92(2H，m)，4.38(2H，s)，3.46(2H，d，J＝7.2)，3.33(2H，s)，2.87-2.91(2H，m)，1.96-2.05(2H，m)，1.5-1.9(3H，m)，1.2-1.4(2H，m)
C) 2-[[1-[2-(2,4 difluorobenzene base)-2-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(213mg 0.533mmol), carries out the operation same with embodiment 1f, obtains the title compound 168mg (yield 72%) of colorless solid to use the compound that obtains among the embodiment 20b.152～157 ℃ of fusing points
1H-NMR(DMSO-d 6)：12.1(1H，s)，9.92(1H，brs)，7.65(1H，d，J＝7.5)，7.45-7.59(4H，m)，7.32-7.39(1H，m)，7.17-7.23(1H，m)，4.48(2H，s)，4.20-4.38(2H，m)，3.3-3.6(4H，m)，2.8-3.0(2H，m)，1.4-2.2(5H，m)
Embodiment 21:(R, S)-5-bromo-2-[[1-[2-(4-fluorophenyl)-2-acetoxyl group ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 105 of table 1)
A) (R, S)-5-bromo-2-[[1-[2-(4-fluorophenyl)-2-acetoxyl group ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 17a (360mg, 0.805mmol), (139mg 1.14mmol) is dissolved in the methylene dichloride (6ml) Dimethylamino pyridine.(100 μ l 1.06mmol), stirred 2 hours under uniform temp the ice-cold acetic anhydride of adding down.Reaction solution dilutes with vinyl acetic monomer, and dried over sodium sulfate is used in water, sodium bicarbonate water, saturated common salt water washing.After filtering insolubles, underpressure distillation removes and desolvates, and obtains the title compound 391mg (yield 99%) of colorless solid.
1H-NMR(CDCl 3)：7.71(1H，d，J＝8.5)，7.58-7.62(2H，m)，7.27-7.33(2H，m)，6.98-7.05(2H，m)，5.89(1H，dd，J＝4.6，8.4)，4.37(2H，s)，3.4-3.5(2H，m)，2.84-3.0(2H，m)，2.80(1H，dd，J＝8.4，13.5)，2.52(1H，dd，J＝4.6，13.5)，2.11(3H，s)，1.9-2.2(2H，m)，1.7-1.8(1H，m)，1.5-1.7(2H，m)，1.2-1.4(2H，m)
B) (R, S)-5-bromo-2-[[1-[2-(4-fluorophenyl)-2-acetoxyl group ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(387mg 0.791mmol), carries out the operation same with embodiment 1f, obtains the title compound 285mg (yield 69%) of colorless solid to use the compound that obtains among the embodiment 21a.193～200 ℃ of fusing points
1H-NMR(DMSO-d 6)：11.0(1H，brs)，7.90(1H，s)，7.69(1H，d，J＝8.1)，7.62(1H，d，J＝8.1)，7.44-7.53(2H，m)，7.22-7.31(2H，m)，6.0-6.2(1H，m)，4.49-4.52(2H，m)，3.2-3.7(6H，m)，2.8-3.0(2H，m)，2.12(3H，s)，1.4-2.0(5H，m)
Embodiment 22:5-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-4,5-dihydro-6H-thieno-[2,3-c] pyrroles-6-keto hydrochloride (compound 776 of table 2)
A) 3-methyl-2-Thiophene Carboxylic Acid ethyl ester
(1.5g 10.55mmol), carries out the operation same with embodiment 3a, obtains the title compound 1.20g of faint yellow oily thing to use 3-methyl-2-Thiophene Carboxylic Acid.It is directly used in following reaction without making with extra care.
B) 3-brooethyl-2-Thiophene Carboxylic Acid ethyl ester
Use the compound 1.20g that obtains among the embodiment 22a, carry out the operation same, obtain the title compound 1.88g of filbert oily thing with embodiment 1b.It is directly used in following reaction without making with extra care.
C) 3-[[1-(tertbutyloxycarbonyl) piperidin-4-yl] the methylamino-methyl]-the 2-Thiophene Carboxylic Acid ethyl ester
Use the compound 1.88g that obtains among the embodiment 22b, carry out the operation same, obtain filbert solid title compound 2.02g with embodiment 1c.It is directly used in following reaction without making with extra care.
D) 3-[[1-(tertbutyloxycarbonyl) piperidin-4-yl] the methylamino-methyl]-2-Thiophene Carboxylic Acid
The compound 1.0g that obtains among the embodiment 22c is dissolved in the ethanol (15ml), add entry (5ml) after, ice-coldly add down sodium hydroxide (400mg 10.0mmol), return room temperature, stirs.After 6 hours, the ice-cold concentrated hydrochloric acid that adds down, the pH value that makes reaction solution is 7.0, uses dichloromethane extraction.Organic layer washes with water, uses dried over mgso.Filter insolubles, filtrate is removed in underpressure distillation, and the solid that obtains is dissolved in the methylene dichloride (3ml), adds ether (20ml), filters and collects the solid of separating out, and obtains title compound 416mg (35%, 3 step).
1H-NMR(CDCl 3)：δ11.4(s，2H)，7.32(d，1H，J＝5.1Hz)，6.91(d，1H，J＝4.5Hz)，4.21(s，2H)，4.04(s，2H)，2.71-2.61(m，4H)，1.96(br s，1H)，1.79(brd，2H，J＝12.6Hz)，1.41(s，9H)，1.16-1.03(m，2H).
E) 4-[(4,5-dihydro-6H-thieno-[2,3-c] pyrroles-6-ketone)-the 2-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
The compound 500mg that obtains among the embodiment 22d is dissolved in the methylene dichloride (14ml), and (0.11ml 1.41mmol), stirs after 1 hour under uniform temp the ice-cold methylsulfonyl chloride of adding down, returns room temperature, stirs 17 hours.Add entry (5ml) in uniform temp downhill reaction liquid, behind dichloromethane extraction, organic layer washes with water, uses dried over mgso.Filter insolubles, filtrate is removed in underpressure distillation, and the oily matter of acquisition is refining with silica gel column chromatography (methyl alcohol-methylene dichloride), obtains light green solid title compound 247mg (yield 52%).
1H-NMR(CDCl 3)：δ7.63(d，1H，J＝4.5Hz)，7.04(d，1H，J＝4.8Hz)，4.33(s，2H)，4.11(br s，2H)，3.45(br s，2H)，2.69(br dd，2H，J＝12.3，12.3Hz)，1.93-1.87(m，1H)，1.67(br d，2H，J＝9.3Hz)，1.45(s，9H)，1.30-1.16(m，2H).
F) 5-(piperidin-4-yl methyl)-4,5-dihydro-6H-thieno-[2,3-c] pyrroles-6-keto hydrochloride
Use compound (310mg 0.90mmol), carries out the operation same with embodiment 1d, the obtains light green solid title compound 200mg) yield 80% that obtains among the embodiment 22e).
1H-NMR(DMSO-d 6)：δ8.90(br s，1H)，8.62(br s，1H)，7.98(d，1H，J＝4.7Hz)，7.24(d，1H，J＝4.7Hz)，4.44(s，2H)，3.38(d，2H，J＝7.4Hz)，3.24(brd，2H，J＝12.6Hz)，2.80(br dd，2H，J＝23.1，12.1Hz)，2.02-1.91(m，1H)，1.74(brd，2H，J＝13.2Hz)，1.43-1.29(m，2H).
G) 5-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-4,5-dihydro-6H-thieno-[2,3-c] pyrroles-6-ketone
(193mg 0.71mmol), carries out the operation same with embodiment 1e, obtains filbert solid title compound 209mg (yield 79%) to use the compound that obtains among the embodiment 22f.
1H-NMR(CDCl 3)：δ8.10-8.04(m，2H)，7.62(d，1H)，7.15-7.07(m，2H)，7.02(m，1H)，4.32(s，2H)，3.72(s，2H)，3.45(d，2H，7.1Hz)，2.96(brd，2H，J＝11.5Hz)，2.20-2.11(m，2H)，1.83-1.76(m，1H)，1.70(brd，2H，J＝13.9Hz)，1.51-1.43(m，2H).
H) 5-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-4,5-dihydro-6H-thieno-[2,3-c] pyrroles-6-keto hydrochloride
(209mg 0.56mmol), carries out the operation same with embodiment 1f, obtains the title compound 178mg (yield 78%) of colorless solid to use the compound that obtains among the embodiment 22g.167～171 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.94(br s，1H)，8.19-8.06(m，2H)，7.99(d，1H，J＝4.8Hz)，7.58(dd，2H，J＝8.9，8.9Hz)，7.26(d，1H，J＝4.5Hz)，5.11-5.04(m，2H)，4.47(s，2H)，3.54(br d 2H，J＝10.5Hz)，3.31(Brs，2H)，3.08-3.01(m，2H)，2.09-1.57(m，5H).
Embodiment 23:6-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone 2 hydrochlorides (compound 796 of table 2)
A) 2-bromo methyl cycloheptapyridine-3-carboxylic acid, ethyl ester
(2.0g 12.11mmol), carries out the operation same with embodiment 1b, obtains the title compound 1.02g of brown oil to use 2-bromo methyl cycloheptapyridine-3-carboxylic acid.It is directly used in following reaction without making with extra care.
B) 4-[(6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone)-the 2-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
Use the compound 1.01g that obtains among the embodiment 23a, carry out the operation same, obtain the title compound 945mg of brown oil with embodiment 1c.It is directly used in following reaction without making with extra care.
C) 6-(piperidin-4-yl methyl)-6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone 2 hydrochlorides
(811mg 1.01mmol), carries out the operation same with embodiment 1d, obtains the title compound 416mg (yield 33%) of colorless solid to use the compound that obtains among the embodiment 23b.
1H-NMR(DMSO-d 6)：δ9.21(s，2H)，8.99(s，2H)，8.10(dd，1H，J＝8.6，1.2Hz)，7.54(dd，1H，J＝7.7，5.0Hz)，4.57(s，2H)，3.47(d，2H，J＝7.4Hz)，3.24(brd，2H，J＝12.3Hz)，2.79(br dd，2H，J＝23.5，12.3Hz)，2.09-1.99(m，1H)，1.75(brd，2H，J＝12.9Hz)，1.46-1.32(m，2H).
D) 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone
(416mg 1.37mmol), carries out the operation same with embodiment 1e, obtains filbert solid title compound 377mg (yield 75%) to use the compound that obtains among the embodiment 23c.
1H-NMR(CDCl 3)：δ8.72(dd，1H，J＝4.7，1.4Hz)，8.13-8.71(m，3H)，7.40(dd，1H，J＝7.6，5.1Hz)，7.12(dd，2H，J＝8.6，8.6Hz)，4.47(s，2H)，3.73(s，2H)，3.55(d，2H，J＝7.1Hz)，2.97(br d，2H，J＝11.5Hz)，2.15(ddd，2H，J＝2.1，11.5，1].5hz)，1.86-1.80(m，1H)，1.70(br d，2H，J＝13.0Hz)，1.56-1.46(m，2H).
E) 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone 2 hydrochlorides
(377mg 1.03mmol), carries out the operation same with embodiment 1f, obtains the title compound 384mg (yield 85%) of colorless solid to use the compound that obtains among the embodiment 23d.138～144 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.1(br s，1H)，8.78(dd，1H，＝4.7，1.1Hz)，8.19(m，3H)，7.57-7.45(m，3H)，5.13-5.05(m，2H)，4.61(s，2H)，3.62(m，3H)，3.32(br s，1H)，3.04(br dd，2H，J＝21.8，10.1Hz)，2.07(br s，1H)，1.89-1.60(m，4H).
Embodiment 24:2-[[1-(3,3-dimethyl-2-oxo butyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 126 of table 1)
A) 2-[[1-(3,3-dimethyl-2-oxo butyl) piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 1d (500mg 1.87mmol) is dissolved among the DMF (6ml), add triethylamine (0.57ml, 4.11ml), 1-chlorine Pinacolone (0.24ml, 1.87ml), at room temperature stir 30 hours after, 50 ℃ of heating 7 hours down.Put cold after, add entry (10ml), use ethyl acetate extraction, organic layer washes with water 3 times, uses dried over mgso.Filter insolubles, filtrate is removed in underpressure distillation, and the oily matter of acquisition is refining with silica gel column chromatography (methyl alcohol-methylene dichloride), obtains filbert solid title compound 369mg (yield 60%).
1H-NMR(CDCl 3)：δ7.84(d，1H，J＝7.2Hz)，7.56-7.42(m，3H)，4.41(s，2H)，3.50(d，2H，J＝7.3Hz)，3.36(s，2H)，2.88(br d，2H，J＝11.3Hz)，2.05(ddd，2H，J＝2.2，11.3，11.3Hz)，1.87-1.80(m，1H)，1.69(br d，2H，J＝12.9Hz)，1.54-1.46(m，2H)，1.15(s，9H).
B) 2-[[1-(3,3-dimethyl-2-oxo butyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(369mg 1.12mmol), carries out the operation same with embodiment 1f, obtains the title compound 323mg (yield 79%) of colorless solid to use the compound that obtains among the embodiment 24a.239～243 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.73(br s，1H)，7.68(d，1H，J＝7.5)，7.61(d，2H)，7.53-7.45(m，1H)，4.64-4.52(m，4H)，3.60-3.21(m，4H)，2.95(br d，2H，J＝10，5Hz)，1.97(br s，1H)，1.79(br d，2H，J＝13.5Hz)，1.65-1.52(m，2H)，1.13(s，9H).
Embodiment 25:2-[[1-(2-methoxy-benzyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 136 of table 1)
A) 2-methoxy-benzyl chlorine
With 2-methoxyl group benzylalcohol (1.01g, 7.31mmol), (757mg 2.55mmol) is dissolved in the tetrahydrofuran (THF) (5ml) triphosgene, ice-coldly adds down pyridine (1.18ml 14.6mmol), is warming up to room temperature.20 minutes after-filtration insolubless, underpressure distillation removes and desolvates then.Oily matter dilutes with vinyl acetic monomer, filters insolubles once more, and underpressure distillation removes and desolvates, and obtains the title compound 1.16g (yield 100%) of yellow oil.
1H-NMR(CDCl 3)：7.25-7.37(2H，m)，6.87-6.97(2H，m)，4.66(2H，s)，3.88(3H，s)
B) 2-[[1-(2-methoxy-benzyl) piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 25a (339mg, 2.17mmol), the compound that obtains among the embodiment 1d (563mg, 2.11mmol) and triethylamine (700 μ l 5.02mmol) add in the dimethyl formamide (6ml), stir 2 hours down at 60 ℃.After reaction solution is cooled to room temperature,, after water, sodium bicarbonate water, the saturated common salt water washing, use dried over sodium sulfate with vinyl acetic monomer, the dilution of hexane mixed solvent.After filtering insolubles, underpressure distillation removes and desolvates, and the solid that obtains is dry-cleaned [け ん washes ] with ether, hexane mixed solvent, with solid drying, obtains the title compound 524mg (yield 71%) of colorless solid.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.2)，7.41-7.53(3H，m)，7.35(1H，dd，J＝1.4，7.7)，7.10-7.26(1H，m)，6.83-6.95(2H，m)，4.40(2H，s)，3.80(3H，s)，3.55(2H，s)，3.50(2H，d，J＝7.2)，2.91-2.96(2H，m)，1.97-2.06(2H，m)，1.5-1.9(3H，m)，1.3-1.5(2H，m)
C) 2-[[1-(2-methoxy-benzyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(521mg 1.49mmol), carries out the operation same with embodiment 1f, obtains the title compound 470mg (yield 82%) of colorless solid to use the compound that obtains among the embodiment 25b.195～203 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.5(1H，brs)，7.58-7.71(4H，m)，7.41-7.51(2H，m)，7.11(1H，d，J＝8.4)，6.98-7.04(1H，m)，4.48-4.52(2H，m)，4.18-4.35(2H，m)，3.82-3.87(3H，m)，3.2-3.5(4H，m)，2.7-2.9(2H，m)，1.5-2.2(5H，m)
Embodiment 26:2-[[1-[2-(2-p-methoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 146 of table 1)
A) methylsulfonic acid 2-anisole ethyl ester
With 2-anisole ethanol (5.29g, 34.74mmol) and triethylamine (7.0ml 50mmol) is dissolved in the tetrahydrofuran (THF) (45ml), ice-coldly adds down methylsulfonyl chloride (3.0ml 39mmol), stirred 1 hour under uniform temp.Reaction solution dilutes with vinyl acetic monomer, after water, 10% aqueous citric acid solution, sodium bicarbonate water, the saturated common salt water washing, uses dried over mgso.After filtering insolubles, underpressure distillation removes and desolvates.The oily matter that obtains is refining with silica gel column chromatography (vinyl acetic monomer-hexane), obtain title compound 5.77g (yield 72%).
1H-NMR(CDCl 3)：7.18-7.29(2H，m)，6.85-6.93(2H，m)，4.42(2H，t，J＝7.1)，3.84(3H，s)，3.07(2H，t，J＝7.1)，2.83(3H，s)
B) 2-[[1-[2-(2-p-methoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound (530mg that obtains among the embodiment 26a, 2.30mmol), the compound that obtains among the embodiment 1d (563mg, 2.11mmol), yellow soda ash (553mg, 5.22mmol) and sodium iodide (328mg, 2.19mmol) add in the N-Methyl pyrrolidone (9ml), stirred 2 hours down at 80 ℃.After reaction solution is cooled to room temperature,, after water, sodium bicarbonate water, the saturated common salt water washing, use dried over sodium sulfate with the vinyl acetic monomer dilution.After filtering insolubles, underpressure distillation removes and desolvates, and the oily matter that obtains is refining with silica gel column chromatography (methylene chloride-methanol), obtains the title compound 544mg (yield 71%) of yellow oil.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.42-7.54(3H，m)，7.12-7.18(2H，m)，6.82-6.90(2H，m)，4.42(2H，s)，3.81(3H，s)，3.52(2H，d，J＝7.2)，3.01-3.06(2H，m)，2.79-2.85(2H，m)，2.51-2.58(2H，m)，1.99-2.08(2H，m)，1.6-1.9(3H，m)，1.3-1.5(2H，m)
C) 2-[[1-[2-(2-p-methoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(533mg 1.46mmol), carries out the operation same with embodiment 1f, obtains the title compound 475mg (yield 81%) of faint yellow solid to use the compound that obtains among the embodiment 26b.208～227 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.3(1H，brs)，7.69(1H，d，J＝7.5)，7.60-7.63(2H，m)，7.48-7.53(1H，m)，7.18-7.26(2H，m)，6.88-7.02(2H，m)，4.51(2H，s)，3.79-3.83(3H，m)，3.1-3.6(6H，m)，2.7-3.0(4H，m)，1.7-2.2(3H，m)，1.5-1.7(2H，m)
Embodiment 27:2-(1-benzyl piepridine-4-ylmethyl) isoindoline-1-keto hydrochloride (compound 176 of table 1)
A) 2-(1-benzyl piepridine-4-ylmethyl) isoindoline-1-ketone
Carry out the operation same, obtain title compound (yield 80%) with embodiment 25b.
1H-NMR(CDCl 3)：δ7.84(d，J＝7.5Hz，1H)，7.41-7.54(m，3H)，7.20-7.30(m，5H)，4.39(s，2H)，3.50(d，J＝6.6Hz，2H)，3.49(s，2H)，2.88(br d，J＝12Hz，2H)，1.96(dt，J＝11.7，2.4Hz，2H)，1.79(m，1H)，1.66(br d，J＝12Hz，2H)，1.41(dq，J＝11.7，3.6Hz，2H).
B) 2-(1-benzyl piepridine-4-ylmethyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 27a, carry out the operation same, obtain title compound (yield 85%) with embodiment 1f.222～229 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ13.50(br s，1H)，7.57-7.60(m，4H)，7.46-7.51(m，4H)，4.50(s，2H)，4.23-4.41(m，2H)，3.40-3.65(m，2H)，2.79-3.34(m，4H)，1.96(m，1H)，1.78(m，2H)，1.55(m，2H).
Embodiment 28:2-[[1-(4-luorobenzyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 186 of table 1)
A) 2-[[1-(4-luorobenzyl) piperidin-4-yl] methyl] isoindoline-1-ketone
Carry out the operation same, obtain title compound (yield 49%) with embodiment 25b.
1H-NMR(CDCl 3)：δ7.84(d，J＝7.5Hz，1H)，7.42-7.53(m，3H)，7.26(m，2H)，6.98(t，J＝8.7Hz，2H)，4.40(s，2H)，3.50(d，J＝7.5Hz，2H)，3.45(s，2H)，2.86(br d，J＝12Hz，2H)，1.94(dt，J＝11.7，2.1Hz，2H)，1.80(m，1H)，1.66(br d，J＝12Hz，2H)，1.40(dq，J＝12，4Hz，2H).
B) 2-[[1-(4-luorobenzyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 28a, carry out the operation same, obtain title compound (yield 85%) with embodiment 1f.241～249 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.30(br s，1H)，7.59-7.69(m，5H)，7.50(m，1H)，7.31(t，J＝9Hz，2H)，4.49(s，2H)，4.25-4.41(m，2H)，3.41-3.64(m，2H)，2.77-3.34(m，4H)，1.96(m，1H)，1.78(br d，J＝12Hz，2H)，1.53(br q，J＝12Hz，2H).
Embodiment 29:2-[[1-[2-(4-fluorophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 196 of table 1)
A) 2-[[1-[2-(4-fluorophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Carry out the operation same, obtain title compound (yield 27%) with embodiment 26b.
1H-NMR(CDCl 3)：δ7.85(d，J＝7.8Hz，1H)，7.43-7.54(m，3H)，7.15(m，2H)，6.96(t，J＝8.4Hz，2H)，4.42(s，2H)，3.52(d，J＝7.2Hz，2H)，2.99(brd，J＝12Hz，2H)，2.77(m，2H)，2.55(m，2H)，2.02(t，J＝11Hz，2H)，1.83(m，1H)，1.73(br d，J＝12Hz，2H)，1.40(dq，J＝12，4Hz，2H).
B) 2-[[1-[2-(4-fluorophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 29a, carry out the operation same, obtain title compound (yield 48%) with embodiment 1f.230～237 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.06(br s，1H)，7.69(d，J＝7.5Hz，1H)，7.61-7.62(m，2H)，7.51(m，1H)，7.32(m，2H)，7.18(t，J＝8.7Hz，2H)，4.52(s，2H)，3.54-3.60(m，2H)，3.42-3.46(m，2H)，2.86-3.34(m，6H)，2.86(m，1H)，1.83(br d，J＝12Hz，2H)，1.54(br q，J＝12Hz，2H).
Embodiment 30:2-[[1-[3-phenyl-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 156 of table 1)
A) 2-[[1-[3-phenyl-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Carry out the operation same, obtain title compound (yield 61%) with embodiment 26b.
1H-NMR(CDCl 3)：δ7.96(d，J＝6.9Hz，2H)，7.85(d，J＝7.2Hz，1H)，7.42-7.59(m，6H)，4.41(s，2H)，3.51(d，J＝6.9Hz，2H)，3.19(t，J＝7.4Hz，2H)，2.96(br t，J＝12Hz，2H)，2.82(t，J＝7.4Hz，2H)，2.04(dt，J＝11.7，1.8Hz，2H)，1.81(m，1H)，1.71(br d，J＝12Hz，2H)，1.40(dq，J＝12，4Hz，2H).
B) 2-[[1-[3-phenyl-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 30a, carry out the operation same, obtain title compound (yield 66%) with embodiment 1f.245～261 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.38(br s，1H)，8.01(d，J＝7.5Hz，2H)，7.69(m，2H)，7.54-7.62(m，4H)，7.49(m，1H)，4.52(s，2H)，2.88-3.70(m，10H)，2.01(m，1H)，1.58(br d，J＝12Hz，2H)，1.51(br q，J＝12Hz，2H).
Embodiment 31:2-[[1-[4-(4-fluorophenyl)-4-oxo butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 166 of table 1)
A) 2-[[1-[4-(4-fluorophenyl)-4-oxo butyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Carry out the operation same, obtain title compound with embodiment 26b.
1H-NMR(CDCl 3)：δ8.00(m，2H)，7.85(d，J＝7.5Hz，1H)，7.42-7.54(m，3H)，7.12(t，J＝8.4Hz，2H)，4.40(s，2H)，3.48(d，J＝7.2Hz，2H)，2.96(t，J＝7.2Hz，2H)，2.90(br d，J＝12Hz，2H)，2.39(t，J＝7.2Hz，2H)，1.90-1.97(m，4H)，1.78(m，1H)，1.66(br d，J＝12Hz，2H)，1.32(dq，J＝12，4Hz，2H).
B) 2-[[1-[4-(4-fluorophenyl)-4-oxo butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 31a, carry out the operation same, obtain title compound (yield 20%) with embodiment 1f.195～199 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.87(br s，1H)，8.06(m，2H)，7.69(d，J＝7.4Hz，1H)，7.60-7.63(m，2H)，7.51(m，1H)，7.38(t，J＝8.8Hz，2H)，4.51(s，2H)，2.85-3.63(m，10H)，1.99-2.04(m，3H)，1.80(br d，J＝12Hz，2H)，1.55(brq，J＝12Hz，2H).
Embodiment 32:2-[[1-[2-(4-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 206 of table 1)
A) 1-(2-chloroethoxy)-4-fluorobenzene
4-fluorophenol (8.92mmol), 1-chloro-2-monobromethane (13.4mmol) are dissolved among the acetone 18mL, add salt of wormwood (12.5mmol), reflux was cooled to room temperature after 10 hours, filtered.Filtrate is concentrated, refining with silica gel column chromatography (hexane/ethyl acetate), obtain title compound (yield 31%).
1H-NMR(CDCl 3)：δ7.02(t，J＝8.6Hz，1H)，6.87(m，2H)，4.19(t，J＝5.8Hz，2H)，3.80(t，J＝5.8Hz，2H).
B) 2-[[1-[2-(4-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 32a, carry out the operation same, obtain title compound (yield 61%) with embodiment 26b.
1H-NMR(CDCl 3)：δ7.85(d，J＝7.2Hz，1H)，7.42-7.54(m，3H)，6.93(t，J＝9Hz，2H)，6.83(m，2H)，4.41(s，2H)，4.05(t，J＝6.0Hz，2H)，3.51(d，J＝7.2Hz，2H)，3.00(br d，J＝12Hz，2H)，2.78(t，J＝6.0Hz，2H)，2.11(dt，J＝11.7，2.1Hz，2H)，1.81(m，1H)，1.69(m，2H)，1.43(dq，J＝12.0，3.6Hz，2H).
C) 2-[[1-[2-(4-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 32b, carry out the operation same, obtain title compound (yield 56%) with embodiment 1f.198～204 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.28(br s，1H)，7.68(d，J＝7.5Hz，1H)，7.60-7.62(m，2H)，7.50(m，1H)，7.16(m，2H)，7.02(m，2H)，4.51(s，2H)，4.36(s，2H)，2.96-3.61(m，8H)，1.99(m，1H)，1.80(m，2H)，1.59(m，2H).
Embodiment 33:2-[[1-[3-(4-fluorophenoxy) propyl group] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 216 of table 1)
A) 1-(3-chlorine propoxy-)-4-fluorobenzene
Carry out the operation same, obtain title compound (yield 94%) with embodiment 32a.
1H-NMR(CDCl 3)：δ6.97(t，J＝8.4Hz，2H)，6.84(m，2H)，4.07(t，J＝6.0Hz，2H)，3.74(t，J＝6.3Hz，2H)，2.22(m，2H).
B) 2-[[1-[3-(4-fluorophenoxy) propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 33a, carry out the operation same, obtain title compound (yield 72%) with embodiment 26b.
1H-NMR(CDCl 3)：δ7.85(d，J＝6.9Hz，1H)，7.42-7.55(m，3H)，6.96(t，J＝8.4Hz，2H)，6.82(m，2H)，4.41(s，2H)，3.96(t，J＝6.3Hz，2H)，3.51(d，J＝7.2Hz，2H)，2.94(br d，J＝12Hz，2H)，2.49(t，J＝7.4Hz，2H)，1.90-1.99(m，4H)，1.81(m，1H)，1.70(m，2H)，1.41(dq，J＝12.3，3.3Hz，2H).
C) 2-[[1-[3-(4-fluorophenoxy) propyl group] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 33b, carry out the operation same, obtain title compound (yield 43%) with embodiment 1f.164 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.14(br s，1H)，7.69(d，J＝7.5Hz，1H)，7.61-7.62(m，2H)，7.51(m，1H)，7.13(t，J＝8.7Hz，2H)，6.95(m，2H)，4.51(s，2H)，4.02(t，J＝6Hz，2H)，2.85-3.64(m，6H)，2.16(m，2H)，1.99(m，1H)，1.80(br d，J＝12Hz，2H)，1.56(br q，J＝12Hz，2H).
Embodiment 34:2-[[1-[4-(4-fluorophenoxy) butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 226 of table 1)
A) 1-(4-chlorine butoxy)-4-fluorobenzene
Carry out the operation same, obtain title compound (yield 97%) with embodiment 32a.
1H-NMR(CDCl 3)：δ6.96(t，J＝8.7Hz，2H)，6.82(m，2H)，3.96(t，J＝5.8Hz，2H)，3.61(t，J＝6.2Hz，2H)，1.89-1.99(m，4H).
B) 2-[[1-[4-(4-fluorophenoxy) butyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 34a, carry out the operation same, obtain title compound (yield 78%) with embodiment 26b.
1H-NMR(CDCl 3)：δ7.85(d，J＝7.5Hz，1H)，7.42-7.53(m，3H)，6.96(t，J＝8.5Hz，2H)，6.81(m，2H)，4.41(s，2H)，3.92(t，J＝6.3Hz，2H)，3.50(d，J＝7.2Hz，2H)，2.93(br d，J＝12Hz，2H)，2.38(t，J＝7.5Hz，2H)，1.93(brt，J＝12Hz，2H)，1.62-1.82(m，7H)，1.40(dq，J＝12，3Hz，2H).
C) 2-[[1-[4-(4-fluorophenoxy) butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 34b, carry out the operation same, obtain title compound (yield 82%) with embodiment 1f.145～146 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.08(br s，1H)，7.69(d，J＝7.5Hz，1H)，7.60-7.62(m，2H)，7.51(m，1H)，7.12(t，J＝9Hz，2H)，6.94(m，2H)，4.51(s，2H)，3.96(t，J＝6Hz，2H)，2.81-3.62(m，8H)，1.99(m，1H)，1.70-1.81(m，6H)，1.55(m，2H).
Embodiment 35:2-[[1-(1-cumarone-2-ylmethyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 236 of table 1)
A) 1-cumarone-2-base methyl alcohol
(467mg 12.3mmol) is suspended in the ether, and heating makes its backflow with lithium aluminum hydride.To wherein splash into 1-cumarone-2-carboxylic acid of being dissolved in the tetrahydrofuran (THF) (10ml) (2.00g, 12.3mmol), reflux 20 minutes.After reaction solution is cooled to 0 ℃, add entry (0.8ml), under uniform temp, stirred 30 minutes.Behind the diatomite filtration insolubles, underpressure distillation removes and desolvates, and obtains the title compound 1.72g (yield 94%) of yellow oil.
1H-NMR(CDCl 3)：7.54-7.58(1H，m)，7.45-7.49(1H，m)，7.19-7.32(2H，m)，6.67(1H，s)，4.78(2H，d，J＝4.5)，1.94(1H，brs)
B) 2-chloromethyl-1-cumarone
(1.00g 6.75mmol), carries out the operation same with embodiment 25a, obtains title compound 1.17g (yield 100%) to use the compound that obtains among the embodiment 35a.
1H-NMR(CDCl 3)：7.47-7.57(2H，m)，7.20-7.20(2H，m)，6.74(1H，s)，4.71(2H，s)
C) 2-[[1-(1-cumarone-2-ylmethyl) piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 35b (538mg, 3.23mmol) and the compound that obtains among the embodiment 1d (783mg 2.94mmol), carries out the operation same with embodiment 25b, obtains the title compound 516mg (yield 49%) of faint yellow solid.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.2)，7.41-7.55(5H，m)，7.19-7.28(2H，m)，6.57(1H，s)，4.39(2H，s)，3.68(2H，s)，3.50(2H，d，J＝6.9)，2.95-3.00(2H，m)，2.03-2.12(2H，m)，1.6-1.9(3H，m)，1.4-1.6(2H，m)
D) 2-[[1-(1-cumarone-2-ylmethyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(277mg 0.769mmol), carries out the operation same with embodiment 1f, obtains the title compound 252mg (yield 83%) of colorless solid to use the compound that obtains among the embodiment 35c.205～213 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.7(1H，brs)，7.58-7.75(5H，m)，7.30-7.51(3H，m)，7.21-7.25(1H，m)，4.56-4.72(2H，m)，4.47-4.51(2H，m)，3.2-3.7(4H，m)，2.8-3.0(2H，m)，1.6-2.2(3H，m)，1.4-1.6(2H，m)
Embodiment 36:2-[[1-[2-(indol-3-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone 1/2 fumarate (compound 241 of table 1)
A) methylsulfonic acid 2-(indol-3-yl) ethyl ester
(2.01g 12.5mmol), carries out the operation same with embodiment 26a, obtains the title compound 3.10g (yield 100%) of dark brown oily matter to use 3-indoles ethanol.
1H-NMR(CDCl 3)：8.11(1H，brs)，7.60(1H，d，J＝7.7)，7.38(1H，d，J＝8.0)，7.10-7.25(3H，m)，4.48(2H，t，J＝7.1)，3.23(2H，t，J＝7.1)，2.85(3H，s)
B) 2-[[1-[2-(indol-3-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 36a (980mg, 3.40mmol) and the compound that obtains among the embodiment 1d (818mg 3.07mmol), carries out the operation same with embodiment 26b, obtains the title compound 465mg (yield 41%) of faint yellow solid.
1H-NMR(CDCl 3)：8.08(1H，brs)，7.86(1H，d，J＝7.2)，7.34-7.62(5H，m)，7.03-7.24(3H，m)，4.42(2H，s)，3.53(2H，d，J＝7.2)，3.08-3.13(2H，m)，2.97-3.03(2H，m)，2.70-2.76(2H，m)，2.06-2.14(2H，m)，1.7-2.0(3H，m)，1.4-1.6(2H，m)
C) 2-[[1-[2-(indol-3-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone 1/2 fumarate
With the compound that obtains among the embodiment 36b (181mg, 0.485mmol) and fumaric acid (61.5mg 0.530mmol) adds in the ethanol (11ml) reflux 30 minutes.Make its drying behind the solid that filtration is separated out, obtain the title compound 108mg (yield 52%) of colorless solid.225～230 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.8(1H，s)，7.68(1H，d，J＝7.5)，7.58-7.61(2H，m)，7.42-7.53(2H，m)，7.33(1H，d，J＝7.8)，7.16(1H，s)，7.03-7.09(1H，m)，6.93-6.99(1H，m)，6.53(1H，s，fumaric acid)，4.50(2H，s)，3.43(2H，d，J＝7.2)，3.08-3.13(2H，m)，2.86-2.90(2H，m)，2.69-2.75(2H，m)，2.14-2.23(2H，m)，1.7-1.9(1H，m)，1.5-1.7(2H，m)，1.2-1.4(2H，m)
Embodiment 37:2-[[1-[(6-fluoro-1,2-benzoisoxazole-3-yl) methyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 246 of table 1)
A) the 2-[[1-[(6-fluoro-1,2-benzoisoxazole-3-yl) methyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(826mg 2.07mmol) is dissolved in the N-Methyl pyrrolidone (7ml), and (243mg 2.17mmol), stirred 3 hours to add potassium tert.-butoxide under the room temperature with the compound that obtains among the embodiment 20b.In reaction solution, add entry, filter the solid of separating out, wash after drying with water, obtain the title compound 573mg (yield 73%) of faint yellow solid.
1H-NMR(CDCl 3)：7.90-7.94(1H，m)，7.84，1H，d，J＝7.8)，7.40-7.55(3H，m)，7.21-7.27(1H，m)，7.03-7.10(1H，m)，4.39(2H，s)，3.88(2H，s)，3.52(2H，d，J＝7.2)，2.89-2.94(2H，m)，2.05-2.15(2H，m)，1.65-1.90(3H，m)，1.3-1.5(2H，m)
B) the 2-[[1-[(6-fluoro-1,2-benzoisoxazole-3-yl) methyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(303mg 0.799mmol), carries out the operation same with embodiment 1f, obtains the title compound 261mg (yield 79%) of colorless solid to use the compound that obtains among the embodiment 37a.175～181 ℃ of fusing points
1H-NMR(DMSO-d 6)：11.1(1H，brs)，8.2-8.3(1H，m)，7.86(1H，d，J＝7.5)，7.67(1H，d，J＝7.2)，7.58-7.61(2H，m)，7.40-7.50(2H，m)，4.82-5.00(2H，m)，4.48(2H，s)，3.59-3.64(2H，m)，3.2-3.5(2H，m)，2.9-3.1(2H，m)，1.4-2.2(5H，m)
Embodiment 38:2-[[1-[2-(1,3-benzo dioxole-5-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 251 of table 1)
A) 1-(1,3-benzo dioxole-5-yl)-2-monobromethane-1-ketone
With 1-(1,3-benzo dioxole-5-yl) ethane-1-ketone (1.05g, 6.40mmol) be dissolved in methylene dichloride (50ml), methyl alcohol (20ml) mixed solvent, add pyridine hydrobromide perbromide [pyridinium perbromide hydrobromide] (2.24g under the room temperature, 7.00mmol), reflux.After 1 hour, decompression distillation down with vinyl acetic monomer, the dilution of hexane mixed solvent, after water, sodium bicarbonate water, the saturated common salt water washing, is used dried over sodium sulfate except that after desolvating.After filtering insolubles, underpressure distillation removes and desolvates, and the solid that obtains is dry-cleaned after drying with hexane, obtains the title compound 1.46g (yield 94%) of faint yellow solid.
1H-NMR(CDCl 3)：7.61(1H，dd，J＝2.2，8.2)，7.46(1H，d，J＝2.2)，6.88(1H，d，J＝8.2)，6.08(2H，s)，4.38(2H，s)
B) 2-[[1-[2-(1,3-benzo dioxole-5-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 38a (491mg, 2.02mmol) and the compound that obtains among the embodiment 1d (507mg 1.90mmol), carries out the operation same with embodiment 1e, obtains the title compound 703mg (yield 94%) of faint yellow solid.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5)，7.67(1H，dd，J＝1.8，8.1)，7.42-7.56(4H，m)，6.84(1H，d，J＝8.1)，6.04(2H，s)，4.41(2H，s)，3.70(2H，s)，3.51(2H，d，J＝7.5)，2.95-3.00(2H，m)，2.1-2.2(2H，m)，1.6-2.0(3H，m)，1.4-1.6(2H，m)
C) 2-[[1-[2-(1,3-benzo dioxole-5-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(690mg 1.76mmol), carries out the operation same with embodiment 1f, obtains the title compound 549mg (yield 73%) of colorless solid to use the compound that obtains among the embodiment 38b.162～166 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.85(1H，brs)，7.47-7.74(6H，m)，7.13-7.19(1H，m)，6.19-6.22(2H，m)，4.95-5.03(2H，m)，4.51-4.54(2H，m)，3.3-3.6(4H，m)，2.9-3.1(2H，m)，2.0-2.2(1H，m)，1.5-1.9(4H，m)
Embodiment 39:2-[[1-[2-(2,3-dihydro-1,4-benzo two oxines [benzodioxine]-6-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 256 of table 1)
A) 2-bromo-1-(2,3-dihydro-1,4-benzo two oxines-6-yl) ethane-1-ketone
(1.42g 7.97mmol), carries out the operation same with embodiment 38a, obtains the title compound 2.05g (yield 100%) of faint yellow solid to use 1-(2,3-dihydro-1,4-benzo two oxines-6-yl) ethane-1-ketone.
1H-NMR(CDCl 3)：7.50-7.54(2H，m)，6.93(1H，m)，4.37(2H，s)，4.32-4.35(2H，m)，4.27-4.31(2H，m)
B) 2-[[1-[2-(2,3-dihydro-1,4-benzo two oxines-6-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 39a (571mg, 2.22mmol) and the compound that obtains among the embodiment 1d (576mg 2.16mmol), carries out the operation same with embodiment 1e, obtains the title compound 627mg (yield 71%) of faint yellow solid.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5)，7.42-7.60(5H，m)，6.89(1H，d，J＝8.4)，4.41(2H，s)，4.26-4.34(4H，m)，3.69(2H，s)，3.51(2H，d，J＝7.2)，2.9-3.0(2H，m)，2.08-2.17(2H，m)，1.6-1.9(3H，m)，1.4-1.6(2H，m)
C) 2-[[1-[2-(2,3-dihydro-1,4-benzo two oxines-6-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(306mg 0.753mmol), carries out the operation same with embodiment 1f, obtains the title compound 263mg (yield 79%) of faint yellow solid to use the compound that obtains among the embodiment 39b.142～150 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.0(1H，brs)，7.69(1H，d，J＝7.5)，7.48-7.62(5H，m)，7.06(1H，d，J＝8.1)，4.97-5.05(2H，m)，4.53(2H，s)，4.2-4.4(4H，m)，3.4-3.7(4H，m)，2.9-3.1(2H，m)，1.5-2.2(5H，m)
Embodiment 40:2-[[1-[(1-cumarone-3-yl) methyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 261 of table 1)
A) (3-methyl isophthalic acid-cumarone-2-yl) carboxylic acid
Will by phenol (10.8g, 114mmol) and sodium hydroxide (4.80g, 114mmol) the sodium phenylate 15.4g of preparation adds in the toluene (160ml).Add 2-chloroacetyl acetacetic ester in the toluene (20ml) be dissolved in reflux (18.6g, 113mmol), heated and stirred 3 hours.Reaction solution is cooled to room temperature, adds entry, extract with toluene.Organic layer is used dried over mgso after using the saturated common salt water washing.After filtering insolubles, underpressure distillation removes and desolvates, and obtains orange 19.7g.It is slowly added in the vitriol oil (20ml) that is cooled to below 5 ℃, under uniform temp, stirred 30 minutes.Reaction solution is added in the frozen water,, after sodium bicarbonate water, saturated common salt water washing, use dried over mgso with vinyl acetic monomer, hexane mixed extractant solvent.After filtering insolubles, underpressure distillation removes and desolvates, and the oily matter that obtains is refining with silica gel column chromatography (vinyl acetic monomer-hexane), obtains orange 7.12g.It is added in 10% potassium hydroxide aqueous solution (50ml) reflux 1 hour.After reaction solution is cooled to room temperature, add 35% sulfuric acid, making the pH value is 1, filters the solid of separating out, and washes with water.With the solid drying that obtains, obtain the title compound 3.16g (yield 16%) of colorless solid.
1H-NMR(CDCl 3)：7.68(1H，d，J＝7.7)，7.58(1H，d，J＝8.3)，7.47-7.53(1H，m)，7.30-7.37(1H，m)，2.65(3H，s)
B) 3-methyl isophthalic acid-cumarone
With the compound that obtains among the embodiment 40a (1.07g 6.07mmol) is dissolved in the quinoline (8ml), add copper powder (410mg, 6.45mmol).Reaction solution is cooled to room temperature in heating under 200 ℃ after 30 minutes, and the insolubles diatomite filtration is used washed with dichloromethane.Mother liquor dilutes with ether, with 10% hydrochloric acid, water, sodium bicarbonate water, saturated common salt water washing, uses dried over mgso.After filtering insolubles, underpressure distillation removes and desolvates, and obtains the title compound 819mg (yield 100%) of dark brown oily matter.
1H-NMR(CDCl 3)：7.51-7.55(1H，m)，7.43-7.47(1H，m)，7.40(1H，s)，7.23-7.31(2H，m)，2.25(3H，s)
C) 2-bromo-3-brooethyl-1-cumarone
With the compound that obtains among the embodiment 40b (771mg, 5.83mmol), N-bromosuccinimide (2.07g, 11.6mmol) and the benzoyl peroxide of catalytic amount add in the tetracol phenixin (20ml) reflux 5 hours.Reaction solution is cooled to room temperature, and behind the filtration insolubles, underpressure distillation removes and desolvates, and obtains the title compound 1.54g (yield 91%) of yellow oil.
1H-NMR(CDCl 3)：7.61-7.65(1H，m)，7.44-7.48(1H，m)，7.30-7.35(2H，m)，4.56(2H，s)
D) methyl 2-[[1-[(2-bromo-1-cumarone-3-yl)] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 40c (1.50g, 5.17mmol) and the compound that obtains among the embodiment 1d (1.55g 5.81mmol), carries out the operation same with embodiment 25b, obtains the title compound 1.67g (yield 74%) of faint yellow solid.
1H-NMR(CDCl 3)：7.83(1H，d，J＝7.2)，7.62-7.70(1H，m)，7.38-7.53(4H，m)，7.20-7.27(2H，m)，4.37(2H，s)，3.59(2H，s)，3.49(2H，d，J＝7.2)，2.90-2.95(2H，m)，1.99-2.08(2H，m)，1.6-1.9(3H，m)，1.3-1.5(2H，m)
E) methyl 2-[[1-[(1-cumarone-3-yl)] piperidin-4-yl] methyl] isoindoline-1-ketone
(460mg when 1.05mmol) being dissolved in tetrahydrofuran (THF) (5ml), ethanol (16ml) mixed solvent, adds the Raney nickel of catalytic amount to the compound that obtains in embodiment 40d, under hydrogen atmosphere, at room temperature stirs 5 hours.The reaction solution diatomite filtration, with tetrahydrofuran (THF), alcohol mixed solvent washing, underpressure distillation removes and desolvates, and obtains the title compound 290mg (yield 77%) of yellow solid.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5)，7.68-7.70(1H，m)，7.42-7.54(5H，m)，7.20-7.31(2H，m)，4.39(2H，s)，3.63(2H，s)，3.50(2H，d，J＝7.5)，2.94-2.99(2H，m)，1.95-2.05(2H，m)，1.6-1.9(3H，m)，1.3-1.5(2H，m)
F) methyl 2-[[1-[(1-cumarone-3-yl)] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
(440mg 1.22mmol), carries out the operation same with embodiment 36c, obtains the title compound 413mg (yield 71%) of colorless solid to use the compound that obtains among the embodiment 40e.226～237 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.91(1H，s)，7.77(1H，d，J＝6.9)，7.66(1H，d，J＝7.5)，7.54-7.59(3H，m)，7.45-7.50(1H，m)，7.24-7.33(2H，m)，6.61(2H，s，fumaricacid)，4.46(2H，s)，3.74(2H，s)，3.40(2H，d，J＝7.5)，2.94-2.99(2H，m)，2.06-2.15(2H，m)，1.7-1.9(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 41:2-[[1-[(2-bromo-1-cumarone-3-yl) methyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 266 of table 1)
(336mg 0.765mmol), carries out the operation same with embodiment 36c, obtains the title compound 305mg (yield 72%) of faint yellow solid to use the compound that obtains among the embodiment 40d.200～211 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.73-7.78(1H，m)，7.66(1H，d，J＝7.5)，7.55-7.60(3H，m)，7.40-7.49(1H，m)，7.26-7.34(2H，m)，6.63(2H，s，fumaric acid)，4.46(2H，s)，3.62(2H，s)，3.39(2H，d，J＝7.5)，2.87-2.92(2H，m)，2.00-2.09(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 42:2-[[1-[2-(4-fluoroanilino)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 271 of table 1)
A) 2-chloro-N-(4-fluorophenyl) ethanamide
Chloroacetyl chloride 0.60ml (7.54mmol) is dissolved in the toluene (6ml), at room temperature adds 4-fluoroaniline 0.72ml (7.52mmol), under uniform temp, stirred 1 hour.In reaction solution, add entry, use ethyl acetate extraction, after the saturated common salt water washing, use dried over mgso.Filter insolubles, filtrate is removed in underpressure distillation, obtains the title compound 1.07g (yield 76%) of faint yellow solid.
1H-NMR(CDCl 3)：8.23(1H，brs，NH)，7.47-7.55(2H，m)，7.02-7.11(2H，m)，4.20(2H，s)
B) 2-[[1-[2-(4-fluoroanilino)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 42a (354mg, 1.89mmol), the compound that obtains among the embodiment 1d (501mg, 1.88mmol) and triethylamine (0.65ml 4.66mmol) adds in the dimethyl formamide (6ml), stirs 3 hours down at 60 ℃.Reaction solution is cooled to room temperature, adds entry, filter and collect the solid of separating out, drying under reduced pressure, the title compound 577mg (yield 81%) of acquisition faint yellow solid.
1H-NMR(CDCl 3)：9.14(1H，brs，NH)，7.86(1H，d，J＝7.5)，7.43-7.57(5H，m)，6.99-7.07(2H，m)，4.42(2H，s)，3.57(2H，d，J＝7.2)，3.10(2H，s)，2.86-2.97(2H，m)，2.19-2.30(2H，m)，1.7-1.9(3H，m)，1.3-1.5(2H，m)
C) 2-[[1-[2-(4-fluoroanilino)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 42b, carry out the operation same, obtain the title compound (yield 70%) of colorless solid with embodiment 1f.201～219 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.9(1H，brs，NH)，9.9(1H，brs，HCl)，7.58-7.71(5H，m)，7.46-7.54(1H，m)，7.21(2H，t，J＝8.7)，4.52(2H，s)，4.25(0.4H，s)，4.14(1.6H，s)，3.3-3.7(4H，m)，2.9-3.1(2H，m)，1.9-2.1(1H，m)，1.7-1.9(2H，m)，1.4-1.6(2H，m)
Embodiment 43:2-[[1-[2-(diphenyl amino)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 278 of table 1)
A) 2-chloro-N, N-phenylbenzene ethanamide
Chloroacetyl chloride 0.32ml (4.02mmol) is dissolved in toluene (6ml)-tetrahydrofuran (THF) (2ml) mixed solvent, at room temperature adds among the pentanoic 690mg (4.08mmol), heated 80 minutes down at 100 ℃.Underpressure distillation removes and desolvates, and with the solid that ether suspension washing is separated out, filtration collection, drying under reduced pressure, obtains the title compound 746mg (yield 75%) of colorless solid.
1H-NMR(CDCl 3)：7.0-7.5(10H，m)，4.03(2H，s)
B) 2-[[1-[2-(diphenyl amino)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 43a, carry out the operation same, obtain the title compound (yield 67%) of faint yellow solid with embodiment 42b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.2)，7.1-7.6(13H，m)，4.38(2H，s)，3.48(2H，d，J＝7.2)，3.10(2H，s)，2.82-2.90(2H，m)，2.04-2.18(2H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
C) 2-[[1-[2-(diphenyl amino)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 43b, carry out the operation same, obtain the title compound (yield 84%) of colorless solid with embodiment 1f.197～209 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.7(1H，brs，HCl)，7.68(1H，d，J＝7.4)，7.2-7.6(13H，m)，4.49(2H，s)，4.10(0.4H，s)，4.02(1.6H，s)，3.3-3.6(4H，m)，2.8-3.0(2H，m)，1.7-1.9(1H，m)，1.6-1.7(2H，m)，1.4-1.6(2H，m)
Embodiment 44:2-[[1-[2-(methylphenylamine base)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 284 of table 1)
A) 2-[[1-[2-(methylphenylamine base)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use methylphenylamine, carry out the operation same, obtain crude product 2-chloro-N-methyl-phenyl acetanilide,Phenacetylaniline with embodiment 43a.Carry out the operation same with it, obtain the title compound (yield 69%) of colorless oil with embodiment 42b.
1H-NMR(CDCl 3)：7.83(1H，d，J＝7.3)，7.16-7.54(8H，m)，4.38(2H，s)，3.46(2H，d，J＝7.2)，3.26(3H，s)，2.92(2H，s)，2.75-2.85(2H，m)，1.9-2.1(2H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
B) 2-[[1-[2-(methylphenylamine base)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 44a, carry out the operation same, obtain the title compound (yield 92%) of colorless solid with embodiment 1f.199～213 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.6(1H，brs，HCl)，7.68(1H，d，J＝7.2)，7.56-7.62(2H，m)，7.2-7.55(6H，m)，4.49(2H，s)，3.9-4.0(2H，m)，3.37(3H，s)，3.1-3.7(4H，m)，2.8-3.0(2H，m)，1.6-1.9(3H，m)，1.3-1.6(2H，m)
Embodiment 45:2-[[1-[3-(4-fluoroanilino)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 274 of table 1)
A) 3-chloro-N-(4-fluorophenyl) propionic acid amide [propane ア ミ De]
Use 4-fluoroaniline and 3-chlorpromazine chloride, carry out the operation same, obtain title compound (yield 57%) with embodiment 42a.
1H-NMR(CDCl 3)：7.3-7.5(3H，m)，6.98-7.05(2H，m)，3.88(2H，t，J＝6.2)，2.81(2H，t，J＝6.2)
B) 2-[[1-[3-(4-fluoroanilino)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 45a, carry out the operation same, obtain the title compound (yield 86%) of faint yellow solid with embodiment 26b.
1H-NMR(CDCl 3)：11.04(1H，s，NH)，7.87(1H，d，J＝7.2)，7.44-7.60(5H，m)，6.96-7.03(2H，m)，4.43(2H，s)，3.58(2H，d，J＝6.9)，3.06-3.12(2H，m)，2.69(2H，t，J＝6.0)，2.51(2H，t，J＝6.0)，2.03-2.14(2H，m)，1.7-2.0(3H，m)，1.3-1.5(2H，m)
C) 2-[[1-[3-(4-fluoroanilino)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 45b, carry out the operation same, obtain the title compound (yield 91%) of colorless solid with embodiment 1f.211～223 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.4(1H，s，NH)，10.2(1H，brs，HCl)，7.59-7.71(5H，m)，7.45-7.53(1H，m)，7.12-7.20(2H，m)，4.51(2H，s)，3.1-3.6(6H，m)，2.8-3.0(4H，m)，1.9-2.1(1H，m)，1.6-1.8(2H，m)，1.4-1.6(2H，m)
Embodiment 46:2-[[1-[3-(diphenyl amino)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 281 of table 1)
A) 2-[[1-[3-(diphenyl amino)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use pentanoic, carry out the operation same, obtain crude product 3-chloro-N, N-diphenylprop acid amides with embodiment 43a.Carry out the operation same with it, obtain the title compound (yield 89%) of colorless solid with embodiment 26b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.4)，7.0-7.6(13H，m)，4.38(2H，s)，3.48(2H，d，J＝7.1)，2.74-2.84(2H，m)，2.73(2H，t，J＝7.5)，2.45(2H，t，J＝7.5)，1.86-1.96(2H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
B) 2-[[1-[3-(diphenyl amino)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 46a, carry out the operation same, obtain the title compound (yield 82%) of colorless solid with embodiment 1f.200～205 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.6-10.2(1H，broad，HCl)，7.68(1H，d，J＝7.5)，7.1-7.65(13H，m)，4.49(2H，s)，3.0-3.6(6H，m)，3.6-3.9(4H，m)，1.8-2.0(1H，m)，1.6-1.8(2H，m)，1.3-1.6(2H，m)
Embodiment 47:2-[[1-[3-(methylphenylamine base)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 287 of table 1)
A) 2-[[1-[3-(methylphenylamine base)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use methylphenylamine, carry out the operation same, obtain crude product 3-chloro-N-methyl-N-Phenylpropionamide with embodiment 43a.Carry out the operation same with it, obtain the title compound (yield 57%) of colorless solid with embodiment 26b.
1H-NMR(CDCl 3)：7.83(1H，d，J＝7.2)，7.3-7.5(6H，m)，7.18(2H，dd，J＝1.4，7.2)，4.37(2H，s)，3.46(2H，d，J＝7.2)，3.26(3H，s)，2.70-2.78(2H，m)，2.65(2H，t，J＝7.5)，2.26(2H，t，J＝7.5)，1.8-2.0(2H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
B) 2-[[1-[3-(methylphenylamine base)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 47a, carry out the operation same, obtain the title compound (yield 91%) of colorless solid with embodiment 1f.206～214 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.5-10.1(1H，broad，HCl)，7.67(1H，d，J＝7.5)，7.55-7.62(2H，m)，7.1-7.5(6H，m)，4.48(2H，s)，3.0-3.6(9H，m)，2.7-2.9(2H，m)，2.5-2.6(2H，m)，1.8-2.0(1H，m)，1.6-1.8(2H，m)，1.3-1.6(2H，m)
Embodiment 48:2-[[1-[2-(1,2,3,4-tetrahydroquinoline-1-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 320 of table 1)
A) 2-[[1-[2-(1,2,3,4-tetrahydroquinoline-1-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 1,2,3, the 4-tetrahydroquinoline carries out the operation same with embodiment 43a, obtains crude product 2-chloro-1-(1,2,3,4-tetrahydroquinoline-1-yl) ethane-1-ketone.Carry out the operation same with it, obtain the title compound (yield 82%) of faint yellow oily thing with embodiment 42b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.2)，7.40-7.54(4H，m)，7.06-7.17(3H，m)，4.38(2H，s)，3.80(2H，t，J＝6.6)，3.48(2H，d，J＝7.2)，3.27(2H，s)，2.86-2.94(2H，m)，2.72(2H，t，J＝6.6)，2.04-2.14(2H，m)，1.92-2.02(2H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
B) 2-[[1-[2-(1,2,3,4-tetrahydroquinoline-1-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 48a, carry out the operation same, obtain the title compound (yield 94%) of colorless solid with embodiment 1f.208～221 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.6(1H，brs，HCl)，7.68(1H，d，J＝7.4)，7.55-7.62(2H，m)，7.45-7.54(1H，m)，7.0-7.4(4H，broad)，4.51(2H，s)，4.1-4.6(2H，broad)，3.2-3.8(8H，m)，2.8-3.0(2H，m)，2.6-2.8(2H，m)，1.5-2.0(7H，m)
Embodiment 49:2-[[1-[3-(1,2,3,4-tetrahydroquinoline-1-yl)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 324 of table 1)
A) 2-[[1-[3-(1,2,3,4-tetrahydroquinoline-1-yl)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 1,2,3, the 4-tetrahydroquinoline carries out the operation same with embodiment 43a, obtains crude product 3-chloro-1-(1,2,3,4-tetrahydroquinoline-1-yl) propane-1-ketone.Carry out the operation same with it, obtain the title compound (yield 79%) of colorless solid with embodiment 26b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.2)，7.40-7.55(3H，m)，7.07-7.25(4H，m)，4.38(2H，s)，3.78(2H，t，J＝6.6)，3.47(2H，d，J＝7.2)，2.6-2.9(8H，m)，1.8-2.0(4H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
B) 2-[[1-[3-(1,2,3,4-tetrahydroquinoline-1-yl)-3-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 49a, carry out the operation same, obtain the title compound (yield 97%) of colorless solid with embodiment 1f.227～232 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.6(1H，brs，HCl)，7.4-7.7(5H，m)，7.0-7.3(3H，m)，4.50(2H，s)，3.6-3.7(2H，m)，3.2-3.6(8H，m)，3.0-3.2(2H，m)，2.8-3.0(2H，m)，2.6-2.8(2H，m)，1.7-2.0(5H，m)，1.3-1.6(2H，m)
Embodiment 50:2-[[1-[2-oxo-2-(piperidines-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 328 of table 1)
A) 2-[[1-[2-oxo-2-(piperidines-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use piperidines, carry out the operation same, obtain crude product 2-chloro-1-(piperidines-1-yl) ethane-1-ketone with embodiment 42a.Carry out the operation same with it, obtain the title compound (yield 73%) of faint yellow oily thing with embodiment 42b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.42-7.54(3H，m)，4.39(2H，s)，3.48-3.55(6H，m)，3.13(2H，s)，2.84-2.91(2H，m)，1.97-2.08(2H，m)，1.4-1.8(9H，m)，1.2-1.4(2H，m)
B) 2-[[1-[2-oxo-2-(piperidines-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 50a, carry out the operation same, obtain the title compound (yield 83%) of colorless solid with embodiment 36c.201～204 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.56-7.61(2H，m)，7.45-7.52(1H，m)，6.59(2H，s，fumaric acid)，4.48(2H，s)，3.3-3.5(6H，m)，3.23(2H，s)，2.83-3.00(2H，m)，2.03-2.14(2H，m)，1.6-1.8(1H，m)，1.3-1.6(8H，m)，1.1-1.3(2H，m)
Embodiment 51:2-[[1-[2-(dihydroindole-1-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 333 of table 1)
A) 2-[[1-[2-(dihydroindole-1-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use dihydroindole, carry out the operation same, obtain crude product 2-chloro-1-(dihydroindole-1-yl) ethane-1-ketone with embodiment 43a.Carry out the operation same with it, obtain the title compound (yield 84%) of faint yellow solid with embodiment 42b.
1H-NMR(CDCl 3)：8.22(1H，d，J＝8.4)，7.84(1H，d，J＝7.2)，7.42-7.56(3H，m)，7.14-7.23(2H，m)，7.14(1H，t，J＝7.7)，4.40(2H，s)，4.19(2H，t，J＝8.4)，3.51(2H，d，J＝7.2)，3.24(2H，s)，3.18(2H，t，J＝8.4)，2.94-3.01(2H，m)，2.12-2.22(2H，m)，1.7-1.9(1H，m)，1.5-1.7(3H，m)，1.3-1.5(2H，m)
B) 2-[[1-[2-(dihydroindole-1-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 51a, carry out the operation same, obtain the title compound (yield 54%) of colorless solid with embodiment 36c.168～171 ℃ of fusing points
1H-NMR(DMSO-d 6)：8.05(1H，d，J＝7.9)，7.67(1H，d，J＝7.4)，7.55-7.62(2H，m)，7.45-7.52(1H，m)，7.24(1H，d，J＝7.3)，7.12-7.18(1H，m)，6.97-7.03(1H，m)，6.61(2H，s，fumaric acid)，4.49(2H，s)，4.17(2H，t，J＝8.4)，3.42(2H，d，J＝7.2)，3.35(2H，s)，3.13(2H，t，J＝8.4)，2.91-2.98(2H，m)，2.15-2.26(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 52:2-[[1-[2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 339 of table 1)
Use 1,2,3, the 4-tetrahydroisoquinoline carries out the operation same with embodiment 42a, obtains crude product 2-chloro-1-(1,2,3,4-tetrahydroisoquinoline-2-yl) ethane-1-ketone.Carry out the operation same with it, obtain crude product 2-[[1-[2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-oxoethyl with embodiment 42b] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound (yield 38%) of colorless solid with embodiment 36c.171～173 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.55-7.61(2H，m)，7.45-7.52(1H，m)，7.0-7.2(4H，m)，6.60(2H，s，fumaric acid)，4.73(0.8H，s)，4.59(1.2H，s)，4.48(1.2H，s)，4.46(0.8H，s)，3.74(1.2H，t，J＝5.7)，3.66(0.8H，t，J＝6.0)，3.32-3.43(4H，m)，2.6-3.0(4H，m)，2.0-2.2(2H，m)，1.6-1.8(1H，m)，1.4-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 53:2-[[1-[2-(dihydroindole-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 338 of table 1)
A) 2-(dihydroindole-1-yl) ethyl acetate
With dihydroindole (1.07g, 8.98mmol), the bromo acetic acid ethyl ester (1.20ml, 10.8mmol), (2.10g 15.2mmol) adds in the dimethyl formamide (14ml) salt of wormwood, 80 ℃ of heating 30 minutes down.
Reaction solution is cooled to room temperature,, washes with water, use dried over sodium sulfate with the vinyl acetic monomer dilution.Filter insolubles, filtrate is removed in underpressure distillation, and the oily matter that obtains is refining with silica gel column chromatography (vinyl acetic monomer-hexane), obtains the title compound 1.35g (yield 73%) of yellow oil.
1H-NMR(CDCl 3)：7.01-7.11(2H，m)，6.68(1H，t，J＝7.4)，6.40(1H，d，J＝7.8)，4.20(2H，q，J＝7.2)，3.88(2H，s)，3.54(2H，t，J＝8.4)，3.03(2H，t，J＝8.4)，1，27(3H，t，J＝7.2)
B) 2-(dihydroindole-1-yl) ethane-1-alcohol
In lithium aluminum hydride 300mg (7.91mmol), add tetrahydrofuran (THF) (9ml), stir down ice-cold.Be dissolved in solution in the tetrahydrofuran (THF) (3ml) to wherein slowly adding the compound 1.33g (6.48mmol) that obtains among the embodiment 53a, under uniform temp, stirred 15 minutes.In reaction solution, add entry (0.3ml), 15% aqueous sodium hydroxide solution (0.3ml), water (0.9ml), sodium sulfate successively.Filter insolubles, filtrate is removed in underpressure distillation, and the oily matter that obtains is refining with silica gel column chromatography (vinyl acetic monomer-hexane), obtains the title compound 873mg (yield 83%) of colorless oil.
1H-NMR(CDCl 3)：7.04-7.13(2H，m)，6.71(1H，t，J＝7.4)，6.57(1H，d，J＝7.8)，3.79-3.84(2H，m)，3.39(2H，t，J＝8.4)，3.21-3.28(2H，m)，3.00(2H，t，J＝8.4)，2.08(1H，brs.OH)
C) 2-[[1-[2-(dihydroindole-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 53b, carry out the operation same, obtain crude product 2-(dihydroindole-1-yl) ethane-1-alcohol methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain crude product 2-[[1-[2-(dihydroindole-1-yl) ethyl with embodiment 26b] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain title compound (yield 66%) with embodiment 36c.216～224 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.55-7.61(2H，m)，7.45-7.52(1H，m)，6.94-7.03(2H，m)，6.58(2H，s，fumaric acid)，6.50-6.56(2H，m)，4.48(2H，s)，3.42(2H，d，J＝7.2)，3.34(2H，t，J＝8.3)，3.22(2H，t，J＝6.9)，3.04-3.11(2H，m)，2.86(2H，t，J＝8.3)，2.70(2H，t，J＝6.9)，2.1-2.3(2H，m)，1.7-1.9(1H，m)，1.5-1.7(2H，m)，1.1-1.4(2H，m)
Embodiment 54:2-[[1-[2-(1,2,3,4-tetrahydroquinoline-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 325 of table 1)
Use 1,2,3, the 4-tetrahydroquinoline carries out the operation same with embodiment 53a, obtains crude product 2-[1, and 2,3,4-tetrahydroquinoline-1-yl] ethyl acetate.Carry out the operation same with it, obtain crude product 2-[1 with embodiment 53b, 2,3,4-tetrahydroquinoline-1-yl] ethane-1-alcohol.Carry out the operation same with it, obtain crude product 2-[1 with embodiment 26a, 2,3,4-tetrahydroquinoline-1-yl] ethane-1-alcohol methanesulfonates.Carry out the operation same with it, obtain crude product 2-[[1-[2-(1,2,3,4-tetrahydroquinoline-1-yl) ethyl with embodiment 26b] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound (yield 46%) of faint yellow solid with embodiment 36c.196～200 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.55-7.61(2H，m)，7.45-7.52(1H，m)，6.90-6.97(1H，m)，6.84(1H，d，J＝6.4)，6.59(2H，s，fumaric acid)，6.56(1H，d，J＝8.3)，6.41-6.48(1H，m)，4.48(2H，s)，3.37-3.44(4H，m)，3.26(2H，t，J＝5.5)，3.00-3.07(2H，m)，2.56-2.68(4H，m)，2.1-2.3(2H，m)，1.7-1.9(3H，m)，1.5-1.7(2H，m)，1.1-1.4(2H，m)
Embodiment 55:5-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-(Z)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (the compound 99Z body of table 1)
A) 5-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-(E, Z)-the oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(443mg 1.12mmol), carries out the operation same with embodiment 18a, obtains title compound (Z body) 239mg (yield 52%) and (E body) 187mg (yield 41%) of colorless solid to use the compound that obtains among the embodiment 3e.
(Z body)
1H-NMR(CDCl 3)：12-13(1H，br，OH)，7.75(1H，d，J＝8.4)，7.56-7.65(2H，m)，6.96-7.08(3H，m)，6.92(1H，d，J＝2.1)，4.35(2H，s)，3.87(3H，s)，3.74(2H，s)，3.48(2H，d，J＝7.2)，3.00-3.07(2H，m)，2.12-2.23(2H，m)，1.8-2.0(1H，m)，1.6-1.8(2H，m)，1.3-1.5(2H，m)
(E body)
1H-NMR(CDCl 3)：7.74(1H，d，J＝8.4)，7.60-7.68(2H，m)，7.05-7.12(2H，m)，6.98(1H，dd，J＝2.1，8.4)，6.91(1H，d，J＝2.1)，4.32(2H，s)，3.86(3H，s)，3.44(2H，d，J＝7.5)，3.31(2H，s)，2.88-2.95(2H，m)，1.95-2.05(2H，m)，1.5-1.9(3H，m)，1.2-1.4(2H，m)
B) 5-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-(Z)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(232mg 0.564mmol), carries out the operation same with embodiment 1f, obtains the title compound 208mg (yield 82%) of colorless solid to use the Z body compound that obtains among the embodiment 55a.173～178 ℃ of fusing points
1H-NMR(DMSO-d 6)：12.61(1H，s，OH)，10.6(1H，brs，HCl)，7.81-7.87(2H，m)，7.56(1H，d，J＝8.4)，7.27-7.34(2H，m)，7.15(1H，d，J＝1.8)，7.02(1H，dd，J＝1.8，8.4)，4.53(0.4H，s)，4.42(2H，s)，4.39(1.6H，s)，3.83(3H，s)，2.9-3.6(6H，m)，1.4-2.0(5H，m)
Embodiment 56:5-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-(E)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (the compound 99E body of table 1)
(180mg 0.438mmol), carries out the operation same with embodiment 1f, obtains the title compound 140mg (yield 71%) of colorless solid to use the E body compound that obtains among the embodiment 55a.192～195 ℃ of fusing points
1H-NMR(DMSO-d 6)：11.86(1H，s，OH)，10.7(1H，brs，HCl)，7.68-7.74(2H，m)，7.57(1H，d，J＝8.4)，7.29-7.37(2H，m)，7.15(1H，d，J＝1.8)，7.03(1H，dd，J＝1.8，8.4)，4.43(2H+0.4H，s)，4.30(1.6H，s)，3.83(3H，s)，3.48-3.55(2H，m)，3.37(2H，d，J＝6.9)，2.90-3.01(2H，m)，1.8-2.0(1H，m)，1.3-1.8(4H，m)
Embodiment 57:5-bromo-2-[[1-[2-(4-fluorophenyl)-2-(Z)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the compound 92Z body of table 1)
A) 5-bromo-2-[[1-[2-(4-fluorophenyl)-2-(E, Z)-the oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(481mg 1.08mmol), carries out the operation same with embodiment 18a, obtains title compound (Z body) 217mg (yield 44%) and (E body) 112mg (yield 23%) of colorless solid to use the compound that obtains among the embodiment 3e.
(Z body)
1H-NMR(CDCl 3)：7.71(1H，d，J＝8.5)，7.56-7.65(4H，m)，7.00-7.08(2H，m)，4.38(2H，s)，3.74(2H，s)，3.49(2H，d，J＝7.3)，3.00-3.07(2H，m)，2.12-2.22(2H，m)，1.8-2.0(1H，m)，1.6-1.8(2H，m)，1.3-1.5(2H，m)
(E body)
1H-NMR(CDCl 3)：7.70(1H，d，J＝8.4)，7.56-7.66(4H，m)，7.04-7.12(2H，m)，4.36(2H，s)，3.46(2H，d，J＝7.5)，3.32(2H，s)，2.90-2.96(2H，m)，1.96-2.07(2H，m)，1.5-1.9(3H，m)，1.2-1.4(2H，m)
B) 5-bromo-2-[[1-[2-(4-fluorophenyl)-2-(Z)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
(212mg 0.461mmol), carries out the operation same with embodiment 36c, obtains the title compound 114mg (yield 43%) of colorless solid to use the Z body compound that obtains among the embodiment 57a.171～174 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.83(1H，s)，7.75-7.82(2H，m)，7.66(1H，d，J＝8.1)，7.58(1H，d，J＝8.1)，7.15-7.22(2H，m)，6.62(2H，s，fumaric acid)，4.45(2H，s)，3.60(2H，s)，3.34(2H，d，J＝7.2)，2.75-2.80(2H，m)，1.96-2.05(2H，m)，1.6-1.8(1H，m)，1.4-1.6(2H，m)，1.0-1.2(2H，m)
Embodiment 58:5-bromo-2-[[1-[2-(4-fluorophenyl)-2-(E)-oximido ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the compound 92E body of table 1)
(109mg 0.237mmol), carries out the operation same with embodiment 36c, obtains the title compound 36mg (yield 26%) of colorless solid to use the E body compound that obtains among the embodiment 57a.186～188 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.98(1H，brs，OH)，7.83(1H，s)，7.61-7.70(3H，m)，7.59(1H，d，J＝8.1)，7.15-7.25(2H，m)，6.62(2H，s，fumaric acid)，4.45(2H，s)，3.35(2H，d，J＝7.2)，3.30(2H，s)，2.77-2.85(2H，m)，1.86-1.97(2H，m)，1.6-1.8(1H，m)，1.4-1.6(2H，m)，1.0-1.2(2H，m)
Embodiment 59:2-[[1-(2-phenylbenzyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 456 of table 1)
A) 2-[[1-(2-phenylbenzyl) piperidin-4-yl] methyl] isoindoline-1-ketone
With 2-phenylbenzyl bromine (462mg, 1.87mmol) and among the embodiment 1d compound dissolution that obtains in dimethyl formamide (6ml), add salt of wormwood (517mg, 1.87mmol), 80 ℃ of following heated and stirred.In reaction solution, add 10ml water, filter and collect the solid of separating out, obtain the title compound 633mg (yield 85%) of colorless solid.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5Hz)，7.53-7.24(12H，m)，4.36(2H，s)，3.47(2H，d，J＝7.2Hz)，3.37(2H，s)，2.78(2H，brd，J＝11.4Hz)，1.83(2H，brdd，J＝11.6，11.6Hz)，1.74-1.68(1H，m)，1.63-1.57(2H，m)，1.39-1.30(2H，m).
B) 2-[[1-(2-phenylbenzyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound 620mg (1.56mmol) that obtains among the embodiment 59a, carry out the operation same, obtain the title compound 331mg (yield 41%) of colorless solid with embodiment 36c.188～193 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67-7.23(13H，m)，6.62(2H，s)，4.45(2H，s)，3.42(2H，s)，3.37(2H，d，J＝6.9Hz)，2.74(2H，brd，J＝11.4Hz)，1.86(2H，brdd，J＝10.8，10.8Hz)，1.69-1.65(1H，m)，1.52(2H，brd，J＝12.6Hz)，1.17(2H，brdd，J＝22.4，10.4Hz).
Embodiment 60:2-[[1-[2-(2-propoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 501 of table 1)
A) 2-hydroxyphenyl ethyl acetate
(6.06g 39.8mmol) is dissolved in the ethanol (180ml), adds the vitriol oil (2ml), reflux 90 minutes with 2-hydroxyphenyl acetate.The concentrating under reduced pressure reaction solution is with vinyl acetic monomer dilution, water, saturated common salt water washing.After dried over sodium sulfate, filter insolubles, concentrating under reduced pressure filtrate, the title compound 7.67g (quantitative yield) of acquisition orange.
1H-NMR(CDCl 3)：7.56(1H，s，OH)，7.15-7.26(1H，m)，7.09(1H，dd，J＝1.5，7.5)，4.20(2H，q，J＝7.2)，3.67(2H，s)，1.29(3H，t，J＝7.2)
B) 2-propoxy-phenylacetic acid ethyl ester
With the compound that obtains among the embodiment 60a (1.12g, 6.22mmol), iodopropane (0.635ml, 6.54mmol), (1.27g 9.19mmol) adds in the dimethyl formamide (10ml) salt of wormwood, 70 ℃ of heating 2 hours down.In reaction solution, add entry, use ethyl acetate extraction, after saturated sodium bicarbonate water, water, saturated common salt water washing, use dried over mgso.Filter insolubles, concentrating under reduced pressure filtrate, the title compound 1.15g (yield 83%) of acquisition yellow oil.
1H-NMR(CDCl 3)：7.15-7.26(2H，m)，6.82-6.93(2H，m)，4.15(2H，q，J＝7.2)，3.92(2H，t，J＝6.4)，3.62(2H，s)，1.72-1.84(2H，m)，1.25(3H，t，J＝7.2)，1.03(3H，t，J＝7.4)
C) 2-[[1-[2-(2-propoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
(1.00g 4.50mmol), carries out the operation same with embodiment 53b, obtains crude product 2-(2-propoxy-phenyl) ethanol (834mg) to use the compound that obtains among the embodiment 60b.Carry out the operation same with it, obtain crude product 2-(2-propoxy-phenyl) ethanol methanesulfonates (1.13g) with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 68%) of faint yellow solid with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.41-7.55(3H，m)，7.11-7.19(2H，m)，6.78-6.89(2H，m)，4.42(2H，s)，3.91(2H，t，J＝6.3)，3.52(2H，d，J＝6.9)，3.00-3.08(2H，m)，2.80-2.88(2H，m)，2.53-2.61(2H，m)，2.0-2.1(2H，m)，1.6-1.9(5H，m)，1.3-1.5(2H，m)，1.04(3H，t，J＝7.4)
D) 2-[[1-[2-(2-propoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 60c, carry out the operation same, obtain the title compound (yield 61%) of colorless solid with embodiment 1f.169～180 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.3-10.7(1H，brs，HCl)，7.69(1H，d，J＝7.4)，7.60-7.63(2H，m)，7.47-7.53(1H，m)，7.18-7.26(2H，m)，6.87-7.00(2H，m)，4.52(2H，s)，3.94(2H，t，J＝6.4)，2.8-3.7(10H，m)，1.9-2.2(1H，m)，1.6-1.9(4H，m)，1.4-1.6(2H，m)，1.01(3H，t，J＝7.4)
Embodiment 61:2-[[1-[2-(2-benzyloxy phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 506 of table 1)
A) 2-[[1-[2-(2-benzyloxy phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound and the bromotoluene that obtain among the embodiment 60a, carry out the operation same, obtain crude product 2-benzyloxy phenylacetic acid ethyl ester with embodiment 60b.Carry out the operation same with it, obtain crude product 2-(2-benzyloxy phenyl) ethanol with embodiment 53b.Carry out the operation same with it, obtain crude product 2-(2-benzyloxy phenyl) ethanol methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 72%) of yellow oil with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.2)，7.28-7.55(8H，m)，7.11-7.19(2H，m)，6.86-6.93(2H，m)，5.07(2H，s)，4.41(2H，s)，3.50(2H，d，J＝7.2)，2.95-3.02(2H，m)，2.83-2.92(2H，m)，2.55-2.63(2H，m)，1.9-2.1(2H，m)，1.5-1.8(3H，m)，1.3-1.5(2H，m)
B) 2-[[1-[2-(2-benzyloxy phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 61a, carry out the operation same, obtain the title compound (yield 56%) of colorless solid with embodiment 36c.184～188 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.68(1H，d，J＝7.5)，7.58-7.62(2H，m)，7.2-7.5(6H，m)，7.1-7.2(2H，m)，7.04(1H，d，J＝8.4)，6.8-6.9(1H，m)，6.57(2H，s，fumaric acid)，5.12(2H，s)，4.48(2H，s)，3.41(2H，d，J＝7.1)，3.0-3.1(2H，m)，2.8-2.9(2H，m)，2.6-2.7(2H，m)，2.1-2.3(2H，m)，1.7-1.9(1H，m)，1.5-1.6(2H，m)，1.2-1.4(2H，m)
Embodiment 62:2-[[1-(2-[1,1 '-biphenyl]-2-base ethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 511 of table 1)
A) 2-[1,1 '-biphenyl]-2-base acetonitrile
With 2-(brooethyl) biphenyl (1.35g, 5.48mmol), potassium cyanide (368mg, 5.65mmol) and the 18-of catalytic amount hat-6 ethers add in the acetonitriles (10ml) reflux 5 days.In reaction solution, add entry, use ethyl acetate extraction, after saturated sodium bicarbonate water, saturated common salt water washing, use dried over mgso.Filter insolubles, concentrating under reduced pressure filtrate, the oily matter that obtains is refining with silica gel column chromatography (vinyl acetic monomer-hexane), the title compound 1.07g (quantitative yield) of acquisition colorless solid.
1H-NMR(CDCl 3)：7.3-7.5(6H，m)，7.2-7.3(3H，m)，3.63(2H，s)
B) 2-[1,1 '-biphenyl]-2-base acetic acid
With the compound that obtains among the embodiment 62a (1.06g 5.48mmol) is dissolved in the ethylene glycol (30ml), to wherein add potassium hydroxide (5.98g, 90.6mmol), 190 ℃ of heating 2 hours down.Reaction solution is cooled to room temperature, injects 1 equivalent hydrochloric acid (200ml).The solid that filtration is separated out, after washing with water, decompression is dry down, obtains the title compound 1.05g (yield 91%) of colorless solid.
1H-NMR(CDCl 3)：7.25-7.42(9H，m)，3.63(2H，s)
C) 2-[[1-[2-(1,1 '-biphenyl)-2-base ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 62b, carry out the operation same, obtain crude product 2-[1 with embodiment 53b, 1 '-biphenyl]-2-base ethanol.Carry out the operation same with it, obtain crude product 2-[1 with embodiment 26a, 1 '-biphenyl]-2-base ethanol methanesulfonates.Carry out the operation same with it, obtain the title compound (yield 70%) of yellow oil with embodiment 26b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.4)，7.1-7.5(12H，m)，4.37(2H，s)，3.45(2H，d，J＝7.0)，2.6-2.8(4H，m)，2.36-2.46(2H，m)，1.5-1.9(7H，m)，1.2-1.4(2H，m)
D) 2-[[1-[2-(1,1 '-biphenyl)-2-base ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 62c, carry out the operation same, obtain the title compound (yield 68%) of colorless solid with embodiment 36c.198～206 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.66(1H，d，J＝7.5)，7.56-7.66(2H，m)，7.1-7.5(10H，m)，6.57(2H，s，fumaric acid)，4.45(2H，s)，3.37(2H，d，J＝7.3)，2.71-2.85(4H，m)，2.50-2.59(2H，m)，1.95-2.10(2H，m)，1.6-1.8(1H，m)，1.4-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 63:2-[[1-[2-(2-benzene oxyethyl group [Off エ ネ チ Le オ キ シ] phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 516 of table 1)
A) 2-[[1-[2-(2-benzene ethoxyl phenenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound and the phenethyl bromide that obtain among the embodiment 60a, carry out the operation same, obtain crude product 2-benzene ethoxyl phenenyl ethyl acetate with embodiment 60b.Carry out the operation same with it, obtain crude product 2-(2-benzene ethoxyl phenenyl) ethanol with embodiment 53b.Carry out the operation same with it, obtain crude product 2-(2-benzene ethoxyl phenenyl) ethanol methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 70%) of yellow oil with embodiment 26b.
1H-NMR(CDCl 3)：7.86(1H，d，J＝7.1)，7.42-7.55(3H，m)，7.11-7.33(7H，m)，6.78-6.89(2H，m)，4.42(2H，s)，4.19(2H，t，J＝6.8)，3.52(2H，d，J＝7.0)，3.10(2H，t，J＝6.8)，2.94-3.01(2H，m)，2.75-2.83(2H，m)，2.46-2.54(2H，m)，1.8-2.0(2H，m)，1.5-1.8(3H，m)，1.3-1.5(2H，m)
B) 2-[[1-[2-(2-benzene ethoxyl phenenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 63a, carry out the operation same, obtain the title compound (yield 56%) of colorless solid with embodiment 36c.178～180 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.68(1H，d，J＝7.5)，7.57-7.62(2H，m)，7.4-7.5(1H，m)，7.10-7.33(7H，m)，6.95(1H，d，J＝8.1)，6.80-6.87(1H，m)，6.57(2H，s，fumaricacid)，4.49(2H，s)，4.20(2H，t，J＝6.3)，3.42(2H，d，J＝7.2)，3.05(2H，t，J＝6.3)，2.94-3.00(2H，m)，2.65-2.72(2H，m)，2.4-2.55(2H，m)，2.0-2.2(2H，m)，1.7-1.8(1H，m)，1.5-1.6(2H，m)，1.2-1.3(2H，m)
Embodiment 64:2-[[1-(2-furyl benzyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 461 of table 1)
A) 2-bromine furans
Dimethyl formamide (35ml) is cooled to-20 ℃, spends 25 minutes and splash into bromine that (13ml 253mmol), is mixed with the dimethyl formamide solution of bromine.
(25ml 345mmol) is dissolved in the dimethyl formamide (35ml), Yi Bian remain on 25～30 ℃, a ray flower splashed into the dimethyl formamide solution of the bromine for preparing in 1 hour, reaction solution was remained on 30～35 ℃ then, stirs 1 hour with furans.Reaction solution is added in the frozen water (230ml), stir after 2 minutes, use extracted with diethyl ether, after washing with water, add Diethyl Aniline (2ml), use dried over sodium sulfate.After filtering insolubles, carry out air distillation, from the cut of 95～105 ℃ of interior temperature, obtain the title compound (yield 23%) of colourless liquid.
1H-NMR(CDCl 3)：7.42(1H，d，J＝2.4Hz)，6.37(1H，d，J＝2.9Hz)，6.30(1H，d，J＝4.0Hz).
B) 2-furyl phenyl aldehyde
With 2-formyl radical phenyl-boron dihydroxide (300mg; 2.0mmol), the 2-bromine furans (588mg that obtains among the embodiment 64a; 4.0mmol) and tetrakis triphenylphosphine palladium [テ ト ラ キ ス ト リ Off エ ニ Le ホ ス Off イ Application パ ラ ジ ウ system] (15mg) be dissolved in the mixed solvent of toluene (38ml) and methyl alcohol (5ml); to wherein adding 2M aqueous sodium carbonate (20ml), 80 ℃ of following heated and stirred 6 hours.Put cold back concentrated solvent, behind dichloromethane extraction, with the mixed solution washing of 2M aqueous sodium carbonate (10ml) and ammonia soln (2ml), use dried over sodium sulfate, after filtering insolubles, filtrate is removed in underpressure distillation, obtains the title compound (126mg) of yellow oily crude product.The crude product that obtains is directly used in following reaction without making with extra care.
C) 2-[[1-(2-furyl benzyl) piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound (267mg that obtains among the embodiment 1d, 1.0ml) be dissolved in the methyl alcohol, add the crude product (126mg) and the sodium cyanoborohydride (157mg that obtain among the embodiment 64b, 2.5mmol), in this reaction solution, add acetic acid (57 μ l, 1.0mmol), make the pH value be about 6,40 ℃ of following heated and stirred 8 hours.Behind the concentrated solvent, dilute with vinyl acetic monomer, with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, use dried over sodium sulfate, after filtering insolubles, filtrate is removed in underpressure distillation, and the crude product that obtains is refining with silica gel column chromatography (methyl alcohol-methylene dichloride), obtain the title compound 165mg (yield 21%, 2 step) of yellow oil.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5Hz)，7.66(1H，dd，J＝7.4，1.7Hz)，7.53-7.43(5H，m)，7.31-7.25(2H，m)，6.75(1H，d，J＝3.0Hz)，6.48(1H，dd，J＝3.3，1.8Hz)，4.39(2H，s)，3.57(2H，s)，3.50(2H，d.J＝7.5Hz)，2.91(2H，brd，J＝11.7Hz)，1.98(2H，ddd，J＝2.1，11.6，11.6Hz)，1.81-1.76(1H，m)，1.65(2H，brd，J＝12.9Hz)，1.41(2H，ddd，J＝3.6，12.0，12.0Hz).
D) 2-[[1-(2-furyl benzyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound 165mg that obtains among the embodiment 64c, carry out the operation same, obtain the title compound 127mg (yield 59%) of colorless solid with embodiment 36c.140～153 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.79(1H，d，J＝1.5Hz)，7.65(2H，d，J＝7.9，7.9Hz)，7.59-7.58(2H，m)，7.49-7.46(2H，m)，7.36-7.32(2H，m)，6.85(1H，d，J＝3.2Hz)，6.63-6.62(3H，m)，4.48(2H，s)，3.64(2H，s)，3.40(2H，d，J＝7.3Hz)，2.84(2H，d，J＝11.5Hz)，2.03(2H，brdd，J＝10.9，10.9Hz)，1.78-1.73(1H，m)，1.58(2H，brdd，J＝11.0Hz)，1.27-1.15(2H，m).
Embodiment 65:2-[[1-(2-benzoyl benzyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 466 of table 1)
A) 2-benzoyl bromotoluene
(1.18g 6.0mmol), carries out the operation same with embodiment 1b, obtains the crude product 1.74g of the title compound of yellow oil to use 2 methyl benzophenone.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-(2-benzoyl benzyl) piperidin-4-yl] methyl] isoindoline-1-ketone
The compound 1.74g that obtains among the embodiment 65a is dissolved in the dimethyl formamide (15ml), add the compound that obtains among the embodiment 1d (1.07g, 4.0mmol) and salt of wormwood (1.10g 8.0mmol), at room temperature stirred 16 hours.In reaction solution, add entry (30ml), use ethyl acetate extraction, water, saturated common salt water washing, after dried over sodium sulfate, filter insolubles, filtrate is removed in underpressure distillation then, and the crude product that obtains is refining with silica gel column chromatography (methyl alcohol-methylene dichloride), obtains the semisolid title compound 1.07g of brown (yield 63%).
1H-NMR(CDCl 3)：7.78-7.75(3H，m)，7.51-7.26(10H，m)，4.28(2H，s)，3.40(2H，s)，3.28(2H，d，J＝6.9Hz)，2.46(2H，d，J＝11.4Hz)，1.79(2H，brdd，J＝11.4，11.4Hz)，1.59-1.56(1H，m)，1.34(2H，brd，J＝13.2Hz)，0.86-0.82(2H，m).
C) 2-[[1-(2-benzoyl benzyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound 1.00g (2.36mmol) that obtains among the embodiment 65b, carry out the reaction same, obtain the title compound 971mg (yield 76%) of colorless solid with embodiment 36c.166～169 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67-7.29(13H，m)，6.63(2H，s)，4.36(2H，s)，3.54(2H，s)，3.18(2H，d，J＝6.9Hz)，2.32(2H，brd，J＝11.1Hz)，1.77(2H，brdd，J＝10.5，10.5Hz)，1.50-1.48(1H，m)，1.25(2H，brd，J＝11.7Hz)，0.67(2H，brdd，J＝20.1，11.7Hz).
Embodiment 66:2-[[1-[3-(2-styroyl phenoxy group) propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 691 of table 1)
A) 2-[3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propoxy-] phenyl aldehyde
Use 2-(3-bromine propoxy-) tetrahydrochysene-2H-pyrans, salicylic aldehyde, carry out the operation same, obtain the title compound (quantitative yield) of colorless oil with embodiment 60b.
1H-NMR(CDCl 3)：10.52(1H，s，OH)，7.83(1H，dd，J＝1.8，7.8)，7.50-7.57(1H，m)，6.98-7.05(2H，m)，4.56-4.61(1H，m)，4.22(2H，t，J＝6.3)，3.91-4.00(1H，m)，3.75-3.85(1H，m)，3.56-3.66(1H，m)，3.38-3.50(1H，m)，2.05-2.22(2H，m)，1.4-1.9(8H，m)
B) 3-(2-styroyl phenoxy group) propyl alcohol
(2.25g 5.19mmol) is suspended in the tetrahydrofuran (THF) (20ml), stirs down ice-cold with benzyl three phenyl phosphonium bromides.(596mg 5.31mol), stirs under uniform temp to wherein adding potassium tert.-butoxide.(1.09g 4.12mmol) is dissolved in solution in the tetrahydrofuran (THF) (4ml), stirs 1 hour to add the compound that obtains among the embodiment 66a in reaction solution.Reaction solution dilutes with 10% aqueous citric acid solution, uses ethyl acetate extraction, after water, saturated sodium bicarbonate water, the saturated common salt water washing, uses dried over mgso.Filter insolubles, concentrating under reduced pressure filtrate obtains crude product 2-[3-[2-[(E, Z)-the 2-phenyl vinyl] phenoxy group] propoxy-] tetrahydrochysene-2H-pyrans.It is dissolved in the methyl alcohol (50ml), adds the tosic acid of catalytic amount, reflux 4 hours.The concentrating under reduced pressure reaction solution, the oily matter that obtains is refining with silica gel column chromatography (vinyl acetic monomer-hexane), obtain 3-[2-[(E, Z)-and the 2-phenyl vinyl] phenoxy group] propyl alcohol.It is dissolved in the ethanol (12ml), adds the 10% palladium/carbon of catalytic amount, under hydrogen atmosphere, stirred 1 hour, obtain the title compound 464mg (yield 45%) of colorless oil.
1H-NMR(CDCl 3)：7.10-7.32(7H，m)，6.85-6.92(2H，m)，4.12(2H，t，J＝5.9)，3.90(2H，t，J＝5.9)，2.8-3.0(4H，m)，2.0-2.2(2H，m)
C) 2-[[1-[3-(2-styroyl phenoxy group) propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 66b, carry out the operation same, obtain crude product 3-(2-styroyl phenoxy group) propyl alcohol methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 86%) of yellow oil with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.40-7.55(3H，m)，7.07-7.29(7H，m)，6.83-6.89(2H，m)，4.41(2H，s)，4.01(2H，t，J＝6.2)，3.51(2H，d，J＝7.2)，2.82-3.00(6H，m)，2.51-2.59(2H，m)，1.9-2.1(4H，m)，1.6-1.9(3H，m)，1.3-1.5(2H，m)
D) 2-[[1-[3-(2-styroyl phenoxy group) propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 66c, carry out the operation same, obtain the title compound (yield 60%) of colorless solid with embodiment 36c.166～169 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.68 (1H, d, J=7.3), 7.57-7.61 (2H, m), 7.4-7.5 (1H, m), 7.11-7.27 (7H, m), 6.93 (1H, d, J=8.0), 6.8-6.9 (1H, m), (6.57 2H, s, fumaric acid), 4.48 (2H, s), 4.00 (2H, t, J=5.9), 3.42 (2H, d, J=7.3), 3.00-3.07 (2H, m), 2.81 (4H, s), and 2.6-2.7 (2H, m), 2.1-2.3 (2H, m), 1.9-2.0 (2H, m), 1.7-1.9 (1H, m), 1.5-1.7 (2H, m), 1.2-1.4 (2H, m)
Embodiment 67:2-[[1-[3-(2-benzyl phenoxy group) propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 696 of table 1)
A) 3-(2-benzyl phenoxy group) propyl alcohol
Use 2-hydroxy diphenyl methane, 3-bromopropyl alcohol, carry out the operation same, obtain the title compound (yield 28%) of colorless oil with embodiment 60b.
1H-NMR(CDCl 3)：7.08-7.28(7H，m)，6.86-6.94(2H，m)，4.08(2H，t，J＝5.7)，3.98(2H，s)，3.71(2H，t，J＝6.0)，1.93-2.03(2H，m)，1.49(1H，brs，OH)
B) 2-[[1-[3-(2-benzyl phenoxy group) propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 67a, carry out the operation same, obtain crude product 3-(2-benzyl phenoxy group) propyl alcohol methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 87%) of faint yellow solid with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.3)，7.41-7.55(3H，m)，7.0-7.3(7H，m)，6.81-6.90(2H，m)，4.40(2H，s)，3.97(2H，t，J＝6.1)，3.96(2H，s)，3.50(2H，d，J＝7.1)，2.84-3.92(2H，m)，2.36-2.44(2H，m)，1.8-2.0(4H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
C) 2-[[1-[3-[2-[2-(3-p-methoxy-phenyl) ethyl] phenoxy group] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 67b, carry out the operation same, obtain the title compound (yield 80%) of colorless solid with embodiment 36c.185～191 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.2)，7.56-7.60(2H，m)，7.46-7.52(1H，m)，7.13-7.27(7H，m)，6.93(1H，d，J＝7.8)，6.83-6.89(1H，m)，6.57(2H，s，fumaricacid)，4.48(2H，s)，3.97(2H，t，J＝6.0)，3.88(2H，s)，3.41(2H，d，J＝7.2)，2.90-2.97(2H，m)，2.48-2.52(2H，m)，2.0-2.15(2H，m)，1.6-1.9(3H，m)，1.5-1.6(2H，m)，1.2-1.3(2H，m)
Embodiment 68:2-[[1-[3-[2-[2-(3-p-methoxy-phenyl) ethyl] phenoxy group] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 701 of table 1)
A) 3-methoxy-benzyl triphenyl phosphonium chloride
With 3-methoxy-benzyl chlorine (1.05g, 6.69mmol), (1.75g 6.67mmol) is dissolved in the dimethyl formamide (10ml) triphenylphosphine, 150 ℃ of down heating 40 minutes.Reaction solution is cooled to room temperature, filters the solid of separating out, after the ether washing, decompression is dry down, obtains the title compound 1.70g (yield 61%) of colorless solid.
1H-NMR(DMSO-d 6)：7.87-7.95(3H，m)，7.64-7.79(12H，m)，7.16(1H，t，J＝7.9)，6.86(1H，d，J＝8.3)，6.61(1H，d，J＝7.4)，6.49(1H，s)，5.1-5.3(2H，m)，3.50(3H，s)
B) 3-[2-[2-(3-p-methoxy-phenyl) ethyl] phenoxy group] propyl alcohol
The compound that obtains among compound that obtains among the use embodiment 68a and the embodiment 66a carries out the operation same with embodiment 66b, obtains the title compound (yield 50%) of colorless oil.
1H-NMR(CDCl 3)：7.10-7.24(3H，m)，6.70-6.93(5H，m)，4.12(2H，t，J＝5.9)，3.90(2H，t，J＝5.9)，3.78(3H，s)，2.8-3.0(4H，m)，2.0-2.2(2H，m)，1.72(1H，brs，OH)
C) 2-[[1-[3-[2-[2-(3-p-methoxy-phenyl) ethyl] phenoxy group] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 68b, carry out the operation same, obtain crude product 3-[2-[2-(3-p-methoxy-phenyl) ethyl with embodiment 26a] phenoxy group] the propyl alcohol methanesulfonates.Carry out the operation same with it, obtain the title compound (yield 84%) of yellow oil with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.42-7.55(3H，m)，7.07-7.22(3H，m)，6.70-6.89(5H，m)，4.41(2H，s)，4.01(2H，t，J＝6.1)，3.77(3H，s)，3.50(2H，d，J＝7.2)，2.80-3.00(6H，m)，2.51-2.59(2H，m)，1.9-2.1(4H，m)，1.6-1.9(3H，m)，1.3-1.5(2H，m)
D) 2-[[1-[3-[2-[2-(3-p-methoxy-phenyl) ethyl] phenoxy group] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 68c, carry out the operation same, obtain the title compound (yield 73%) of colorless solid with embodiment 36c.181～184 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.4)，7.58-7.60(2H，m)，7.47-7.51(1H，m)，7.12-7.20(3H，m)，6.93(1H，d，J＝8.0)，6.70-6.87(4H，m)，6.57(2H，s，fumaricacid)，4.48(2H，s)，4.00(2H，t，J＝5.8)，3.70(3H，s)，3.41(2H，d，J＝7.2)，2.98-3.05(2H，m)，2.7-2.9(4H，m)，2.6-2.7(2H，m)，2.0-2.2(2H，m)，1.9-2.0(2H，m)，1.7-1.8(1H，m)，1.5-1.7(2H，m)，1.2-1.4(2H，m)
Embodiment 69:2-[[1-[4-phenyl-2-oxo butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 344 of table 1)
In being cooled to-78 ℃ DME (3mL), add 2M LDA/ heptane, THF, EtPh solution 3.07mL (6.14mmol), then splash into benzyl acetone 0.700g (4.72mmol)/DME (5mL).Stir after 1 hour, splash into a chlorine trimethyl silane 0.779mL (6.14mmol), be warming up to room temperature.Reaction solution dilutes with hexane, water * 2, saturated NH 4Na is used in the Cl aqueous solution * 2, salt water washing 2SO 4Dry.
After distillation removes and to desolvate, the oily matter of remnants is dissolved among the THF (18mL), is cooled to 0 ℃, add NBS 0.924g (5.19mmol).Be warming up to room temperature, stir after 1 hour, reaction solution is injected Na 4S 2O 3In the aqueous solution, use extracted with diethyl ether 3 times, with the organic layer Na that merges 2SO 4Dry.
Distillation is dissolved in the oily matter that obtains among the DMF (10mL) after removing and desolvating, and adds embodiment 1d) middle compound 1.26g (4.72mmol) and the triethylamine 1.64mL (11.8mmol) that obtains, after at room temperature stirring, reaction solution dilutes with vinyl acetic monomer, and Na is used in water * 4, salt water washing 2SO 4Dry.
The filtering siccative after concentrating, is made the solution of ethanol 1.5mL and vinyl acetic monomer 3mL, adds 4N HCl-AcOEt 1.08mL (4.31mmol), after the stirring, adds vinyl acetic monomer 10mL, the crystallization that filtering is separated out, and drying obtains title compound (yield 39%).183～187 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.93(br s，1H)，7.68(d，J＝7.4Hz，1H)，7.61(m，2H)，7.49(m，1H)，7.16-7.31(m，5H)，4.51(s，2H)，4.33-4.50(m，2H)，2.84-3.57(m，10H)，1.99(m，1H)，1.78(br d，J＝13Hz，2H)，1.58(m，2H).
Embodiment 70:2-[[1-[3-phenyl-2-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 349 of table 1)
A) 2-[[1-[3-phenyl-2-hydroxypropyl] piperidin-4-yl] methyl] isoindoline-1-ketone
The compound 994mg (3.73mmol) and (2, the 3-epoxypropyl) benzene 0.500g (3.73mmol), the triethylamine 0.78mL (5.60mmol) that obtain among the embodiment 1d are dissolved in the 8mL ethanol, are heated to 50 ℃.After reaction finished, reaction solution diluted with vinyl acetic monomer, and Na is used in water * 4, saturated common salt water washing 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (acetone), obtain title compound (yield 44%).
1H-NMR(CDCl 3)：δ7.85(d，J＝7.2Hz，1H)，7.42-7.56(m，3H)，7.21-7.32(m，5H)，4.39(s，2H)，3.90(m，1H)，3.49(d，J＝9.6Hz，2H)，2.96(br d，J＝9Hz，1H)，2.76-2.86(m，2H)，2.65(m，1H)，2.20-2.31(m，3H)，1.87(dt，J＝12，2Hz，1H)，1.79(m，1H)，1.67(br d，J＝13Hz，2H)，1.36(dq，J＝12，4Hz，2H).
B) 2-[[1-[3-phenyl-2-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With (COCl) 20.125g (0.998mmol)/CH 2Cl 23mL is cooled to-78 ℃, splashes into DMSO 0.121g (1.55mmol), stirs after 10 minutes, splashes into embodiment 70a) middle compound 180mg (the 0.494mmol)/CH that obtains 2Cl 21mL.Stir after 30 minutes, splash into triethylamine 0.491mL (3.52mmol), stir after 4 hours, be warming up to room temperature.Reaction solution dilutes with vinyl acetic monomer 40mL, and Na is used in water * 4, saturated common salt water washing 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (acetone/hexane), obtain title compound (yield 50%).
1H-NMR(CDCl 3)：δ7.85(d，J＝7.5Hz，1H)，7.42-7.54(m，3H)，7.22-7.35(m，5H)，4.40(s，2H)，3.75(s，2H)，3.51(d，J＝7.2Hz，2H)，3.16(s，2H)，2.79(br d，J＝12Hz，2H)，2.03(dt，J＝11.4，2.1Hz，2H)，1.78(m，1H)，1.67(br d，J＝10Hz，2H)，1.47(dq，J＝12，4Hz，2H).
C) 2-[[1-[3-phenyl-2-oxopropyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 70b, carry out the operation same, obtain title compound (yield 59%) with embodiment 1f.198～204 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.84(br s，1H)，7.68(d，J＝7.5Hz，1H)，7.61(m，2H)，7.50(m，1H)，7.22-7.37(m，5H)，4.40-4.54(m，4H)，3.88(s，2H)，2.94-3.56(m，6H)，1.99(m，1H)，1.78(br d，J＝14Hz，2H)，1.56(m，2H).
Embodiment 71:2-[[1-[4-phenyl-3-oxo butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 354 of table 1)
A) 1-tosyloxy-3-hydroxy-4-phenyl propane
Will according to document (yonemitsu, people such as O., " organic synthesis " (Org.Synth.), 1984,63,198.) synthetic methyl (phenyl acetyl) acetic acid 0.700g (3.64mmol)/24mL ethanolic soln is cooled to 0 ℃, adds NaBH 41.10g (29.1mmol), at room temperature stir.In reaction solution, add concentrated hydrochloric acid, be acid, with the saturated aqueous common salt dilution, use dichloromethane extraction 4 times, the organic layer Na that merges 2SO 4Dry.
The filtering siccative after concentrating, is dissolved in the oily matter that obtains among the methylene dichloride 8mL, adds pyridine 0.61mL (7.54mmol), is cooled to 0 ℃.Add toluene sulfonyl chloride 0.694g (3.64mmol) in this stirred solution, stir after 2 hours, reaction solution dilutes with ether, washes with water 2 times, uses Na 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (vinyl acetic monomer/hexane), obtain title compound (yield 32%).
1H-NMR(CDCl 3)：δ7.78(d，J＝8.1Hz，2H)，7.15-7.34(m，7H)，4.26(m，1H)，4.17(m，1H)，3.94(m，1H)，2.78(m，1H)，2.64(m，1H)，2.44(s，3H)，1.93(m，1H)，1.75(m，1H).
B) 2-[[1-[4-phenyl-3-oxo butyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 71a, carry out the operation same with embodiment 26b, with the compound that obtains without carry out the operation same, acquisition title compound (yield 27%) refiningly with embodiment 70b.
1H-NMR(CDCl 3)：δ7.84(d，J＝7.2Hz，1H)，7.44-7.53(m，3H)，7.18-7.32(m，5H)，4.39(s，2H)，3.70(s，2H)，3.48(d，J＝7.2Hz，2H)，2.82(br d，J＝12Hz，2H)，2.05-2.65(m，4H)，1.91(dt，J＝11.7，2.1Hz，2H)，1.75(m，1H)，1.66(m，2H)，1.33(dq，J＝12，3Hz，2H).
C) 2-[[1-[4-phenyl-3-oxo butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 71b, carry out the operation same, obtain title compound (yield 61%) with embodiment 1f.163～166 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.89(br s，1H)，7.68(d，J＝7.5Hz，1H)，7.61(m，2H)，7.49(m，1H)，7.19-7.35(m，5H)，4.50(s，2H)，3.84(s，2H)，2.81-3.62(m，10H)，1.97(m，1H)，1.78(br d，J＝13Hz，2H)，1.49(m，2H).
Embodiment 72:2-[[1-[2-(2-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 376 of table 1)
A) 2-[[1-[2-(2-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With 2 '-methoxyacetophenone (1.11g, 7.39mmol), (2.61g 8.16mmol) is dissolved in methylene dichloride (50ml)-methyl alcohol (20ml) mixed solvent reflux 1 hour to the pyridine hydrobromide perbromide.Reaction solvent is removed in underpressure distillation, with the vinyl acetic monomer dilution, after water, the saturated common salt water washing, uses dried over mgso.After filtering insolubles, filtrate is removed in underpressure distillation, obtains crude product 2-bromo-1-(2-p-methoxy-phenyl) ethane-1-ketone.Carry out the operation same with it, obtain the title compound (yield 63%) of yellow oil with embodiment 1e.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5)，7.70(1H，dd，J＝2.0，7.7)，7.42-7.55(4H，m)，6.93-7.03(2H，m)，4.41(2H，s)，3.89(3H，s)，3.80(2H，s)，3.50(2H，d，J＝7.2)，2.92-3.00(2H，m)，2.14-2.26(2H，m)，1.6-1.9(3H，m)，1.4-1.55(2H，m)
B) 2-[[1-[2-(2-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 72a, carry out the operation same, obtain the title compound (yield 50%) of colorless solid with embodiment 36c.180～190 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.44-7.61(5H，m)，7.17(1H，d，J＝8.2)，7.03(1H，t，J＝7.4)，6.60(2H，s，fumaric acid)，4.48(2H，s)，3.88(3H，s)，3.84(2H，s)，3.40(2H，d，J＝7.3)，2.88-2.95(2H，m)，2.21-2.31(2H，m)，1.6-1.8(1H，m)，1.4-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 73:2-[[1-[2-(4-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 396 of table 1)
A) 2-[[1-[2-(4-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 2-bromo-1-(4-aminomethyl phenyl) ethane-1-ketone, carry out the operation same, obtain the title compound (yield 83%) of faint yellow solid with embodiment 1e.
1H-NMR(CDCl 3)：7.91(2H，d，J＝8.2)，7.84(1H，d，J＝7.5)，7.41-7.59(3H，m)，7.24(2H，d，J＝8.2)，4.41(2H，s)，3.76(2H，s)，3.51(2H，d，J＝7.1)，2.95-3.03(2H，m)，2.41(3H，s)，2.09-2.21(2H，m)，1.6-1.9(3H，m)，1.4-1.6(2H，m)
B) 2-[[1-[2-(4-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 73a, carry out the operation same, obtain the title compound (yield 90%) of colorless solid with embodiment 1f.169～185 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.8-10.0(1H，brs，HCl)，7.80(0.5H，d，J＝7.9)，7.89(1.5H，d，J＝7.9)，7.69(1H，d，J＝7.4)，7.57-7.63(2H，m)，7.40-7.52(3H，m)，5.09(0.5H，s)，5.02(1.5H，s)，4.53(2H，s)，3.51-3.58(2H，m)，3.47(2H，d，J＝7.0)，2.9-3.1(2H，m)，2.41(3H，s)，1.9-2.1(1H，m)，1.4-1.9(4H，m)
Embodiment 74:2-[[1-[2-(3, the 4-difluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 401 of table 1)
A) 2-[[1-[2-(3, the 4-difluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 3 ', 4 '-difluoro acetophenone, carry out and embodiment 72a, the same operation of embodiment 1e, obtain the title compound (yield 84%) of yellow solid.
1H-NMR(CDCl 3)：7.8-8.0(3H，m)，7.40-7.57(3H，m)，7.10-7.26(1H，m)，4.40(2H，s)，3.67(2H，s)，3.51(2H，d，J＝7.2)，2.86-2.97(2H，m)，2.08-2.20(2H，m)，1.6-1.9(3H，m)，1.3-1.5(2H，m)
B) 2-[[1-[2-(3, the 4-difluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 74a, carry out the operation same, obtain the title compound (yield 79%) of colorless solid with embodiment 36c.186～193 ℃ of fusing points
1H-NMR(DMSO-d 6)：8.00-8.09(1H，m)，7.85-7.95(1H，m)，7.54-7.69(4H，m)，7.4-7.5(1H，m)，6.62(2H，s，fumaric acid)，4.48(2H，s)，3.83(2H，s)，3.40(2H，d，J＝7.2)，2.84-2.90(2H，m)，2.08-2.18(2H，m)，1.6-1.8(1H，m)，1.4-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 75:2-[[1-[2-(2-naphthyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 411 of table 1)
A) 2-[[1-[2-(2-naphthyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 2-bromo-1-(2-naphthyl) ethane-1-ketone, carry out the operation same, obtain the title compound (yield 83%) of faint yellow solid with embodiment 1e.
1H-NMR(CDCl 3)：8.57(1H，s)，7.83-8.05(4H，m)，7.41-7.66(6H，m)，4.42(2H，s)，3.96(2H，s)，3.53(2H，d，J＝7.2)，3.04-3.13(2H，m)，2.20-2.31(2H，m)，1.6-1.9(3H，m)，1.4-1.6(2H，m)
B) 2-[[1-[2-(2-naphthyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 75a, carry out the operation same, obtain the title compound (yield 61%) of faint yellow solid with embodiment 1f.192～201 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.8-10.2(1H，brs，HCl)，8.81(0.2H，s)，8.72(0.8H，s)，7.97-8.19(4H，m)，7.4-7.8(6H，m)，5.26(0.4H，s)，5.19(1.6H，s)，4.55(2H，s)，3.57-3.64(2H，m)，3.49(2H，d，J＝6.9)，3.0-3.2(2H，m)，2.0-2.2(1H，m)，1.5-1.9(4H，m)
Embodiment 76:2-[[1-[2-(3-chloro-phenyl-)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 406 of table 1)
A) 2-[[1-[2-(3-chloro-phenyl-)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 3 '-chloro-acetophenone, carry out and embodiment 72a, the same operation of embodiment 1e, obtain the title compound (yield 79%) of orange.
1H-NMR(CDCl 3)：7.98-8.00(1H，m)，7.90(1H，d，J＝8.1)，7.85(1H，d，J＝7.5)，7.3-7.6(5H，m)，4.41(2H，s)，3.74(2H，s)，3.52(2H，d，J＝7.4)，2.94-3.02(2H，m)，2.08-2.20(2H，m)，1.6-1.9(3H，m)，1.3-1.5(2H，m)
B) 2-[[1-[2-(3-chloro-phenyl-)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 76a, carry out the operation same, obtain the title compound (yield 64%) of colorless solid with embodiment 36c.187～193 ℃ of fusing points
1H-NMR(DMSO-d 6)：8.00(1H，d，J＝1.5)，7.97(1H，d，J＝8.4)，7.64-7.74(2H，m)，7.4-7.6(4H，m)，6.61(2H，s，fumaric acid)，4.48(2H，s)，3.88(2H，s)，3.40(2H，d，J＝7.2)，2.86-2.92(2H，m)，2.10-2.21(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 77:2-[[1-[2-(2-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 386 of table 1)
A) 2-[[1-[2-(2-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 2 '-methyl acetophenone, carry out and embodiment 72a, the same operation of embodiment 1e, obtain the title compound (yield 78%) of orange.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5)，7.33-7.66(5H，m)，7.20-7.27(2H，m)，4.41(2H，s)，3.75(2H，s)，3.52(2H，d，J＝7.2)，2.99-3.07(2H，m)，2.48(3H，s)，2.1-2.3(2H，m)，1.8-2.0(1H，m)，1.6-1.8(2H，m)，1.4-1.6(2H，m)
B) 2-[[1-[2-(2-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 77a, carry out the operation same, obtain the title compound (yield 56%) of colorless solid with embodiment 36c.186～194 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.75 (1H, d, J=7.2), 7.66 (1H, d, J=7.5), 7.55-7.60 (2H, m), 7.39-7.51 (2H, m), 7.30 (2H, t, J=7.1), 6.61 (2H, s, fumaric acid), 4.47 (2H, s), 3.79 (2H, s), 3.39 (2H, d, J=7.2), 2.86-2.93 (2H, m), 2.38 (3H, s), 2.12-2.23 (2H, m), 1.6-1.8 (1H, m), and 1.5-1.6 (2H, m), 1.1-1.3 (2H, m)
Embodiment 78:2-[[1-[2-(3-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 391 of table 1)
A) 2-[[1-[2-(3-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 3 '-methyl acetophenone, carry out and embodiment 72a, the same operation of embodiment 1e, obtain the title compound (yield 58%) of yellow oil.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5)，7.77-7.82(2H，m)，7.26-7.56(5H，m)，4.41(2H，s)，3.82(2H，s)，3.52(2H，d，J＝7.2)，2.99-3.06(2H，m)，2.40(3H，s)，2.18-2.30(2H，m)，1.8-2.0(1H，m)，1.6-1.8(2H，m)，1.4-1.6(2H，m)
B) 2-[[1-[2-(3-toluyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 78a, carry out the operation same, obtain the title compound (yield 55%) of colorless solid with embodiment 36c.185～193 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.77-7.82(2H，m)，7.67(1H，d，J＝7.5)，7.55-7.60(2H，m)，7.35-7.52(3H，m)，6.61(2H，s，fumaric acid)，4.48(2H，s)，3.88(2H，s)，3.41(2H，d，J＝7.3)，2.8-3.0(2H，m)，2.37(3H，s)，2.0-2.2(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 79:2-[[1-[2-(3-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 381 of table 1)
A) 2-[[1-[2-(3-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 2-bromo-1-(3-p-methoxy-phenyl) ethane-1-ketone, carry out the operation same, obtain the title compound (yield 90%) of yellow oil with embodiment 1e.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.2)，7.40-7.65(5H，m)，7.35(1H，t，J＝8.0)，7.08-7.19(1H，m)，4.41(2H，s)，3.85(3H，s)，3.80(2H，s)，3.52(2H，d，J＝7.2)，2.97-3.06(2H，m)，2.15-2.29(2H，m)，1.6-1.9(3H，m)，1.4-1.6(2H，m)
B) 2-[[1-[2-(3-p-methoxy-phenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 79a, carry out the operation same, obtain the title compound (yield 71%) of colorless solid with embodiment 36c.178～188 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.55-7.61(3H，m)，7.40-7.52(3H，m)，7.21(1H，dd，J＝2.3，8.1)，6.61(2H，s，fumaric acid)，4.48(2H，s)，3.87(2H，s)，3.81(3H，s)，3.41(2H，d，J＝7.2)，2.8-3.0(2H，m)，2.0-2.2(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 80:5-methoxyl group-2-[[1-(2-phenyl-2-oxoethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 42 of table 1)
A) 5-methoxyl group-2-[[1-(2-phenyl-2～oxoethyl) piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound and the phenacyl bromide that obtain among the embodiment 9c, carry out the operation same, obtain the title compound (yield 55%) of faint yellow oily thing with embodiment 1e.
1H-NMR(CDCl 3)：8.01(2H，d，J＝7.2)，7.75(1H，dd，J＝2.6，8.7)，7.53-7.61(1H，m)，7.45(2H，t，J＝7.5)，6.96-7.00(1H，m)，6.92(1H，s)，4.36(2H，s)，3.88(3H，s)，3.82(2H，s)，3.48(2H，d，J＝7.2)，2.97-3.05(2H，m)，2.15-2.27(2H，m)，1.6-1.9(3H，m)，1.4-1.6(2H，m)
B) 5-methoxyl group-2-[[1-(2-phenyl-2-oxoethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 80a, carry out the operation same, obtain the title compound (yield 74%) of colorless solid with embodiment 36c.186～193 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.99(2H，d，J＝7.5)，7.66(1H，t，J＝7.5)，7.49-7.62(3H，m)，7.13(1H，d，J＝1.5)，7.02(1H，dd，J＝2.1，8.4)，6.61(2H，s，fumaric acid)，4.41(2H，s)，3.89(2H，s)，3.83(3H，s)，3.36(2H，d，J＝7.2)，2.88-2.95(2H，m)，2.12-2.23(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 81:2-[[1-[2-(2-furyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-keto hydrochloride (compound 416 of table 1)
A) 2-bromo-1-(2-furyl)-ethane-1-ketone
(500mg 4.54mmol), carries out the reaction same with embodiment 72a, obtains colourless semisolid title compound 119mg (yield 14%) to use the 2-acetyl furan.
1H-NMR(CDCl 3)：7.65(1H，s)，7.35(1H，d，J＝3.9Hz)，4.33(2H，s).
B) 2-[[1-[2-(2-furyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-ketone
Use the compound that obtains among the embodiment 81a (119mg, 0.63mmol) and the compound that obtains among the embodiment 1d (160mg 0.60mmol), carries out the reaction same with embodiment 1e, obtains the crude product 131mg of title compound.The crude product that obtains is directly used in following reaction without making with extra care.
C) 2-[[1-[2-(2-furyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-keto hydrochloride
Use the crude product 131mg that obtains among the embodiment 81b, carry out the reaction same, obtain the title compound 40mg (yield 18%, 2 step) of colorless solid with embodiment 1f.209～216 (decomposition)
1H-NMR(DMSO-d 6)：9.98(1H，brs)，8.17(1H，s)，7.74-7.58(4H，m)，7.53-7.47(1H，m)，6.85(1H，d，J＝3.5Hz)，4.87-4.78(2H，m)，4.52(2H，s)，3.60-3.44(4H，m)，3.05-2.98(2H，m)，2.01(1H，brs)，1.83(2H，brd，J＝13.9Hz)，1.64(2H，brdd，J＝11.1，11.1Hz).
Embodiment 82:2-[[1-[2-(2-thienyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-keto hydrochloride (compound 421 of table 1)
A) 2-bromo-1-(2-thienyl)-ethane-1-ketone and 2-bromo-1-(5-bromine 2-thienyl)-ethane-1-ketone
Use 2-acetyl thiophene (500mg; 3.96mmol); carry out the reaction same with embodiment 72a; refining with silica gel column chromatography, obtain 2-bromo-1-(the 2-thienyl)-ethane-1-ketone 618mg (yield 76%) of faint yellow oily thing and 2-bromo-1-(the 5-bromine 2-thienyl)-ethane-1-ketone 171mg (yield 15%) of faint yellow oily thing.
2-bromo-1-(2-thienyl)-ethane-1-ketone
1H-NMR(CDCl 3)：7.82(1H，d，J＝3.6Hz)，7.73(1H，d，J＝4.0Hz)，7.18(1H，dd，J＝5.2，3.8Hz)，4.37(2H，s).
2-bromo-1-(5-bromine 2-thienyl)-ethane-1-ketone
1H-NMR(CDCl 3)：7.55(1H，g，J＝3.8Hz)，7.14(1H，d，J＝3.8Hz)，4.28(2H，s).
B) 2-[[1[-2-(2-thienyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-ketone
Use 2-bromo-1-(the 2-thienyl)-ethane-1-ketone (300mg that obtains among the embodiment 82a, 1.46mmol) and embodiment 1d in the compound (389mg that obtains, 1.46mmol), carry out the reaction same with embodiment 1e, obtain the title compound 441mg (yield 85%) of colorless solid.
1H-NMR(CDCl 3)：7.98(1H，dd，J＝3.8，1.1Hz)，7.85(1H，d，J＝7.5Hz)，7.62-7.61(1H，m)，7.56-7.43(3H，m)，7.13-7.10(1H，m)，4.41(2H，s)，3.58(2H，s)，3.53(2H，d，J＝7.3Hz)，2.96(2H，brd，J＝11.5Hz)，2.17(2H，ddd，J＝2.4，11.5，11.5Hz)，1.84-1.78(1H，m)，1.70-1.67(2H，m)，1.53(2H，ddd，J＝3.6，12.0，12.0Hz).
C) 2-[[1-[2-(2-thienyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-keto hydrochloride
(435mg 1.23mmol), carries out the reaction same with embodiment 1f, obtains the title compound 418mg (yield 87%) of colorless solid to use the compound that obtains among the embodiment 82b.182～186 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.1(1H，brs)，8.18(1H，d，J＝1.8Hz)，8.05(1H，d，J＝3.3Hz)，7.69(1H，d，J＝7.2Hz)，7.62-7.58(2H，m)，7.53-7.47(1H，m)，7.36-7.34(1H，m)，5.04-4.95(2H，m)，4.53(2H，s)，3.55(2H，brd，J＝11.7Hz)，3.46(2H，brd，J＝6.9Hz)，3.05(2H，brs)，2.03(1H，brs)，1.86-1.63(4H，m).
Embodiment 83:2-[[1-[2-(5-bromo-2-thienyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-keto hydrochloride (compound 426 of table 1)
A) 2-[[1-[2-(5-bromo-2-thienyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-ketone
(171mg 0.602mmol), carries out the reaction same with embodiment 1e, obtains the crude product (210mg) of filbert solid title compound to use 2-bromo-1-(the 5-bromine 2-thienyl)-ethane-1-ketone that obtains among the embodiment 82a.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(5-bromo-2-thienyl)-2-oxoethyl] piperidin-4-yl] methyl]-isoindoline-1-keto hydrochloride
Use the crude product (171mg) that obtains among the embodiment 83a, carry out the reaction same, obtain filbert solid title compound 99mg (yield 38%, 2 step) with embodiment 1f.195～208 ℃ of fusing points (decomposition)
1H-NMR(DMSO-d 6)：10.1(1H，brs)，8.03-7.89(1H，m)，7.70-7.47(5H，m)，5.01-4.90(2H，m)，4.52(2H，s)，3.58-3.44(4H，m)，3.04-2.97(2H，m)，2.03-1.60(5H，m).
Embodiment 84:2-[[1-(2-cyclohexyl-2-oxoethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 446 of table 1)
A) 2-chloro-1-(1-cyclohexyl) ethane-1-ketone
Use the hexahydrobenzoic acid methyl esters, the halogenated ketone synthesis method preparation according to the record of international publication number WO/23756 communique obtains title compound (yield 79%).
1H-NMR(CDCl 3)：4.16(2H，s)，2.58-2.69(1H，m)，1.6-1.9(4H，m)，1.1-1.5(6H，m)
B) 2-[[1-(2-cyclohexyl-2-oxoethyl) piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 84a, carry out the operation same, obtain the title compound (yield 51%) of colorless oil with embodiment 1e.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.2)，7.41-7.56(3H，m)，4.40(2H，s)，3.50(2H，d，J＝7.2)，3.20(2H，s)，2.81-2.88(2H，m)，2.41-2.50(1H，m)，1.98-2.09(2H，m)，1.6-1.9(7H，m)，1.1-1.5(8H，m)
C) 2-[[1-(2-cyclohexyl-2-oxoethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 84b, carry out the operation same, obtain the title compound (yield 89%) of colorless solid with embodiment 36c.186～196 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.55-7.60(2H，m)，7.45-7.52(1H，m)，6.61(2H，s，fumaric acid)，4.48(2H，s)，3.41(2H，d，J＝7.4)，3.29(2H，s)，2.75-2.81(2H，m)，2.4-2.6(1H，m)，2.0-2.2(2H，m)，1.53-1.76(8H，m)，1.0-1.3(7H，m)
Embodiment 85:2-[[1-(2-cyclohexyl-2-hydroxyethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 451 of table 1)
A) 2-[[1-(2-cyclohexyl-2-hydroxyethyl) piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 84b, carry out the operation same, obtain the title compound (yield 77%) of colorless solid with embodiment 16a.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.42-7.57(3H，m)，4.40(2H，s)，3.48-3.53(2H，m)，3.35-3.45(1H，m)，3.0-3.1(1H，m)，2.7-2.8(1H，m)，2.2-2.4(3H，m)，1.5-2.0(9H，m)，0.9-1.5(8H，m)
B) 2-[[1-(2-cyclohexyl-2-hydroxyethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 85a, carry out the operation same, obtain the title compound (yield 85%) of colorless solid with embodiment 36c.180～183 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.2)，7.55-7.62(2H，m)，7.44-7.52(1H，m)，6.53(2H，s，fumaric acid)，4.49(2H，s)，3.45-3.60(1H，m)，3.42(2H，d，J＝7.2)，3.0-3.2(2H，m)，2.5-2.7(2H，m)，2.2-2.4(2H，m)，0.90-2.0(17H，m)
Embodiment 86:2-[[1-[[5-(4-chloro-phenyl-)] furfuryl group] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 471 of table 1)
A) 2-[[1-[[5-(4-chloro-phenyl-)] furfuryl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Add acetic acid in methyl alcohol (5mL) solution of compound 334mg (1.45mmol), 5-(4-chloro-phenyl-) the furfural 300mg (1.45mmol) that obtains in embodiment 1d, making its pH value is 6, adds NaCNBH 30.25g (3.58mmol), after at room temperature stirring 4 hours, distillation for removing methanol with the vinyl acetic monomer dilution, is used saturated NaHCO then 3Na is used in the aqueous solution * 2, saturated common salt water washing 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (methylene chloride), obtain title compound (yield 55%).
1H-NMR(CDCl 3)：δ7.84(d，J＝7.2Hz，1H)，7.57(d，J＝8.7Hz，2H)，7.43-7.53(m，3H)，7.32(d，J＝8.7Hz，2H)，6.56(d，J＝3.5Hz，1H)，6.26(d，J＝3.5Hz，1H)，4.39(s，2H)，3.61(s，2H)，3.50(d，J＝6.9Hz，2H)，2.96(br d，J＝11.4Hz，2H)，2.07(dt，J＝11.4，2.1Hz，2H)，1.78(m，1H)，1.70(br d，J＝12Hz，2H)，1.43(dq，J＝11.4，3.3Hz，2H).
B) 2-[[1-[[5-(4-chloro-phenyl-)] furfuryl group] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 86a, carry out the operation same, obtain title compound (yield 82%) with embodiment 1f.218～226 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.6(br s，1H)，7.78(d，J＝8.4Hz，2H)，7.67(d，J＝7.5Hz，1H)，7.58(m，2H)，7.46-7.54(m，3H)，7.08(d，J＝3Hz，1H)，6.83(d，J＝3Hz，1H)，4.41-4.49(m，4H)，2.88-3.43(m，6H)，1.98(m，1H)，1.80(br d，J＝13Hz，2H)，1.56(br q，J＝12Hz，2H).
Embodiment 87:2-[[1-[[2-(1-phenyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 476 of table 1)
A) 2-formyl radical-1-phenylpyrrole, 3-formyl radical-1-phenylpyrrole
DMF 561mg (7.68mmol) is cooled to 0 ℃, splashes into POCl31.18g (7.68mmol).After at room temperature stirring 15 minutes, splash into 1-phenylpyrrole 1.00g (6.98mmol)/DMF 1.6mL solution.After stirring 1.5 hours under 50 ℃, be cooled to 0 ℃, add saturated Na 2CO 3The aqueous solution, make pH be 8 after, with vinyl acetic monomer dilution, separate organic layer, it is washed with water 3 times, use Na 2SO 4Dry.The filtering siccative after concentrating, with silica gel chromatography (dichloromethane/hexane) separation and purification, obtains title compound.
2-formyl radical-1-phenylpyrrole (yield 86%)
1H-NMR(CDCl 3)：δ9.57(s，1H)，7.43-7.47(m，5H)，7.17(dd，J＝3.9，1.5Hz，1H)，7.08(t，J＝1.8Hz，1H)，6.41(dd，J＝3.9，2.6Hz，1H).
3-formyl radical-1-phenylpyrrole (yield 14%)
1H-NMR(CDCl 3)：δ9.86(s，1H)，7.67(t，J＝1.8Hz，1H)，7.37-7.49(m，5H)，7.09(t，J＝2.4Hz，1H)，6.81(dd，J＝3.0，1.5Hz，1H).
B) 2-[[1-[[2-(1-phenyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound 2-formyl radical-1-phenylpyrrole that obtains among the embodiment 87a, carry out the operation same, obtain title compound (yield 64%) with embodiment 86a.
1H-NMR(CDCl 3)：δ7.85(d，J＝7.5Hz，1H)，7.31-7.56(m，8H)，6.84(t，J＝2.4Hz，1H)，6.22(t，J＝3.0Hz，1H)，6.17(dd，J＝3.3，1.8Hz，1H)，4.38(s，2H)，3.48(d，J＝7.2Hz，2H)，3.31(s，2H)，2.86(d，J＝11.4Hz，2H)，1.86(dt，J＝11.4，1.8Hz，2H)，1.74(m，1H)，1.61(br d，J＝12.9Hz，2H)，1.30(dq，J＝12，3.6Hz，2H).
C) 2-[[1-[[2-(1-phenyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 87b, carry out the operation same, obtain title compound (yield 75%) with embodiment 40f.281～284 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.66(d，J＝7.5Hz，1H)，7.45-7.62(m，7H)，7.36(t，J＝7Hz，1H)，6.96(t，J＝2Hz，1H)，6.62(s，2H)，6.16(br s，2H)，4.46(s，2H)，3.37-3.39(m，4H)，2.81(d，J＝11Hz，2H)，1.93(m，2H)，1.71(m，1H)，1.55(br d，J＝12Hz，2H)，1.15(br q，J＝11Hz，2H).
Embodiment 88:2-[[1-[[3-(1-phenyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 481 of table 1)
A) 2-[[1-[[3-(1-phenyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound 3-formyl radical-1-phenylpyrrole that obtains among the embodiment 87a, carry out the operation same, obtain title compound (yield 85%) with embodiment 86a.
1H-NMR(CDCl 3)：δ7.84(d，J＝7.2Hz，1H)，7.35-7.54(m，7H)，7.21(m，1H)，7.01(m，2H)，6.27(m，1H)，4.40(s，2H)，3.50-3.52(m，4H)，3.02(br d，J＝11.7Hz，2H)，2.03(dt，J＝11.7，2.1Hz，2H)，1.83(m，1H)，1.71(br d，J＝12Hz，2H)，1.45(dq，J＝11.7，3.6Hz，2H).
B) 2-[[1-[[3-(1-phenyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 88b, carry out the operation same, obtain title compound (yield 81%) with embodiment 40f.222～227 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.67(d，J＝7.4Hz，1H)，7.42-7.58(m，7H)，7.35(s，2H)，7.24(t，J＝7.2Hz，1H)，6.55(s，2H)，6.26(s，1H)，4.48(s，2H)，3.66(s，2H)，3.42(d，J＝7.2Hz，2H)，3.08(d，J＝11.7Hz，2H)，2.28(br t，J＝11Hz，2H)，1.82(m，1H)，1.65(br d，J＝12Hz，2H)，1.33(br q，J＝11Hz，2H).
Embodiment 89:2-[[1-[[2-(1-benzyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 486 of table 1)
A) 2-formyl radical-1-benzyl-pyrrole
At N 2Under 0 ℃, in the stirred suspension of 60%NaH 252mg (6.31mmol)/DMF 8mL, splash into pyrroles-2-carboxyl aldehyde 0.500g (5.26mmol)/DMF 4mL down.Stir after 10 minutes, splash into bromotoluene 0.75mL (6.31mmol).Stir after 30 minutes, reaction solution dilutes with vinyl acetic monomer, and Na is used in water * 4, saturated common salt water washing 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (dichloromethane/hexane), obtain title compound (yield 99%).
1H-NMR(CDCl 3)：δ9.56(s，1H)，7.23-7.34(m，3H)，7.15(d，J＝7.2Hz，2H)，6.98(m，2H)，6.27(m，1H)，5.57(s，2H).
B) 2-[[1-[[2-(1-benzyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 89a, carry out the operation same, obtain title compound (yield 52%) with embodiment 86a.
1H-NMR(CDCl 3)：δ7.85(d，J＝7.2Hz，1H)，7.42-7.55(m，3H)，7.21-7.31(m，3H)，7.03(d，J＝7.2Hz，2H)，6.66(m，1H)，6.08(m，1H)，6.00(dd，J＝3.0，1.5Hz，1H)，5.22(s，2H)，4.37(s，2H)，3.46(d，J＝7.5Hz，2H)，3.26(s，2H)，2.79(d，J＝11.7Hz，2H)，1.82(dt，J＝11.7，1.8Hz，2H)，1.72(m，1H)，1.58(br d，J＝12Hz，2H)，1.23(dq，J＝12.0，3.6Hz，2H).
C) 2-[[1-[[2-(1-benzyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 89b, carry out the operation same, obtain title compound (yield 84%) with embodiment 1f.171 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.33(br s，1H)，7.68(d，J＝7.5Hz，1H)，7.60(m，2H)，7.49(m，1H)，7.26-7.35(m，3H)，7.02-7.08(m，2H)，6.95(s，1H)，6.42(m，1H)，6.14(m，1H)，5.35-5.40(m，2H)，4.50(s，2H)，4.14-4.29(m，2H)，2.79-3.64(m，4H)，1.94(m，1H)，1.76(m，2H)，1.59(m，2H).
Embodiment 90:2-[[1-[[2-(1-butyl) pyrryl] methyl] piperidin-4-yl]
Methyl] isoindoline-1-keto hydrochloride (compound 491 of table 1)
A) 2-formyl radical-1-butyl pyrroles
Use n-BuI, carry out the operation same, obtain title compound (yield 92%) with embodiment 89a.
1H-NMR(CDCl 3)：δ9.53(s，1H)，6.91-6.94(m，2H)，6.21(dd，J＝3.9，2.4Hz，1H)，4.31(t，J＝7.2Hz，2H)，1.74(m，2H)，1.29(m，2H)，0.93(t，J＝7.2Hz，3H).
B) 2-[[1-[[2-(1-butyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 90a, carry out the operation same, obtain title compound (yield 29%) with embodiment 86a.
1H-NMR(CDCl 3)：δ7.84(d，J＝7.5Hz，1H)，7.42-7.55(m，3H)，6.62(t，J＝1.8Hz，1H)，6.02(t，J＝3.3Hz，1H)，5.93(dd，J＝3.3，1.8Hz，1H)，4.39(s，2H)，3.92(t，J＝7.5Hz，2H)，3.49(d，J＝7.5Hz，2H)，3.39(s，2H)，2.85(br d，J＝11.7Hz，2H)，1.87(dt，J＝11.7，2.1Hz，2H)，1.63-1.75(m，5H)，1.28-1.38(m，4H)，0.94(t，J＝7.5Hz，3H).
C) 2-[[1-[[2-(1-butyl) pyrryl] methyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 90b, carry out the operation same, obtain title compound (yield 78%) with embodiment 1f.179 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.04(br s，1H)，7.68(d，J＝7.5Hz，1H)，7.59-7.61(m，2H)，7.49(m，1H)，6.90(s，1H)，6.35(m，1H)，6.07(m，1H)，4.50(s，2H)，4.23-4.37(m，2H)，3.96-4.04(m，2H)，2.84-3.66(m，6H)，1.95(m，1H)，1.78(br d，J＝12Hz，2H)，1.54-1.62(m，4H)，1.21(m，2H)，0.87(t，J＝7.5Hz，3H).
Embodiment 91:2-[[1-[(2-pyrryl) methyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 496 of table 1)
Carry out the operation same, obtain title compound (60%) with embodiment 86a, 1f.186 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ11.09(br s，1H)，9.99(br s，1H)，7.65(d，J＝7.5Hz，1H)，7.59(m，2H)，7.48(m，1H)，6.89(s，1H)，6.23(m，1H)，6.08(s，1H)，4.49(s，2H)，4.18-4.33(m，2H)，2.73-3.60(m，6H)，1.94(m，1H)，1.76(br d，J＝12Hz，2H)，1.48(br q，J＝12Hz，2H).
Embodiment 92:2-[[1-[2-(2-phenyl-1H-imidazoles-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone 2 hydrochlorides (compound 591 of table 1)
A) t-butyldimethylsilyl 2-(2-phenyl-1H-imidazoles-1-yl) ethyl ether
With ethylene bromohyrin (3.44g, 27.53mmol), TERT-BUTYL DIMETHYL CHLORO SILANE (4.23g, 28.07mmol) and imidazoles (3.97g 58.31mmol) is dissolved in the dimethyl formamide (20ml), at room temperature stirs 3 hours.Reaction solution dilutes with vinyl acetic monomer, after water, the saturated common salt water washing, uses dried over mgso.After filtering insolubles, concentrating under reduced pressure filtrate obtains crude product t-butyldimethylsilyl 2-bromotrifluoromethane ether (6.05g).With this crude product (1.83g), 2-phenylimidazole (1.11g, 7.70mmol) and salt of wormwood (1.50g 10.9mmol) adds in the dimethyl formamide (10ml), 80 ℃ of heating 10 hours down.The reaction solution dilute with water is used ethyl acetate extraction.After its water, saturated common salt water washing, use dried over sodium sulfate.After filtering insolubles, concentrating under reduced pressure filtrate is made with extra care the oily matter that obtains with silica gel column chromatography (vinyl acetic monomer-hexane), obtain the title compound 1.16g (yield 50%) of faint yellow oily thing.
1H-NMR(CDCl 3)：7.62-7.68(2H，m)，7.43-7.49(3H，m)，7.18(1H，d，J＝1.2)，7.13(1H，d，J＝1.2)，4.14(2H，t，J＝5.4)，3.87(2H，t，J＝5.4)，0.84(9H，s)，-0.04(6H，s)
B) 2-(2-phenyl-1H-imidazoles-1-yl) ethane-1-alcohol
(1.11g 3.67mmol) is dissolved in the ethanol (8ml), ice-coldly stirs down with the compound that obtains among the embodiment 92a.To wherein adding 18% aqueous hydrochloric acid (10ml), under uniform temp, stirred 2 hours.The reaction solution hexane wash adds sodium hydroxide in water layer, make its pH value greater than 11.Behind dichloromethane extraction, use dried over sodium sulfate.Filter insolubles, concentrating under reduced pressure filtrate, the solid that obtains suspends with ether and washs, and obtains the title compound 636mg (yield 92%) of colorless solid.
1H-NMR(CDCl 3)：7.55-7.61(2H，m)，7.38-7.42(3H，m)，7.07(1H，s)，7.05(1H，s)，4.11(2H，t，J＝5.4)，3.87(2H，t，J＝5.4)，2.85(1H，brs，OH)
C) 2-[[1-[2-(2-phenyl-1H-imidazoles-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 92b, carry out the operation same, obtain crude product 2-(2-phenyl-1H-imidazoles-1-yl) ethane-1-alcohol methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 50%) of yellow oil with embodiment 26b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.2)，7.37-7.62(8H，m)，7.11(1H，d，J＝0.9)，7.10(1H，d，J＝0.9)，4.38(2H，s)，4.08(2H，t，J＝6.8)，3.47(2H，d，J＝7.2)，2.75-2.82(2H，m)，2.64(2H，t，J＝6.8)，1.9-2.0(2H，m)，1.5-1.9(3H，m)，1.2-1.4(2H，m)
D) 2-[[1-[2-(2-phenyl-1H-imidazoles-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone 2 hydrochlorides
Use the compound that obtains among the embodiment 92c, carry out the operation same, obtain the title compound (yield 90%) of colorless solid with embodiment 1f.155～168 ℃ of fusing points
1H-NMR(DMSO-d 6)：13.0(1H，brs，HCl)，11.5(1H，brs，HCl)，8.04-8.10(1H，m)，7.81-7.89(3H，m)，7.57-7.76(6H，m)，7.45-7.54(1H，m)，4.60-4.69(2H，m)，4.49(2H，s)，3.0-3.7(6H，m)，2.7-2.9(2H，m)，1.4-1.8(5H，m)
Embodiment 93:2-[[1-[2-[2-(1-benzyl) pyrryl]-the 2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 431 of table 1)
Use the 2-acetyl pyrrole, carry out the operation same with embodiment 89a, synthetic 1-benzyl-2-acetyl pyrrole is without carry out the operation same with embodiment 69, acquisition title compound (yield 8%) refiningly.196～200 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.71(br s，1H)，7.68(d，J＝7.8Hz，1H)，7.61(m，2H)，7.57(m，1H)，7.49(m，1H)，7.23-7.33(m，4H)，7.08(m，2H)，6.35(m，1H)，5.59(s，2H)，4.69-4.78(m，2H)，4.51(s，2H)，2.89-3.56(m，6H)，1.97(m，1H)，1.79(m，2H)，1.58(m，2H).
Embodiment 94:2-[[1-[2-[2-(1-butyl) pyrryl]-the 2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 436 of table 1)
Use the 2-acetyl pyrrole, carry out the operation same with embodiment 90a, synthetic 1-butyl-2-acetyl pyrrole is without carry out the operation same with embodiment 69, acquisition title compound (yield 67%) refiningly.200～207 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.78(br s，1H)，7.69(d，J＝7.5Hz，1H)，7.61(m，2H)，7.51(m，1H)，7.40(m，1H)，7.20(m，1H)，6.25(m，1H)，4.70-4.78(m，2H)，4.53(s，2H)，4.30(t，J＝7.2Hz，2H)，2.52-3.51(m，6H)，1.94(m，1H)，1.82(br d，J＝12Hz，2H)，1.25(m，2H)，0.88(t，J＝7.5Hz，3H).
Embodiment 95:2-[[1-[2-[2-(1-phenyl) pyrryl]-the 2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 441 of table 1)
A) 2-[[1-[2-[2-(1-phenyl) pyrryl]-the 2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use is carried out the operation same with embodiment 1e according to document (P.D.Croce, C.L.Rosa, A.Ritieni, Synthesis, 1989,783.) synthetic 1-phenyl-2-chloracetyl pyrroles, obtains title compound (yield 52%).
1H-NMR(CDCl 3)：δ7.84(d，J＝7.2Hz，1H)，7.34-7.57(m，6H)，7.21-7.25(m，3H)，6.95(m，1H)，6.29(m，1H)，4.38(s，2H)，3.61(s，2H)，3.48(d，J＝7.2Hz，2H)，2.94(br d，J＝11Hz，2H)，2.12(dt，J＝11.4，2.4Hz，2H)，1.80(m，1H)，1.65(br d，J＝12Hz，2H)，1.45(dq，J＝12，3Hz，2H).
B) 2-[[1-[2-[2-(1-phenyl) pyrryl]-the 2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 95a, carry out the operation same, obtain title compound (yield 89%) with embodiment 1f.193～197 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.75(br s，1H)，7.65(d，J＝7.5Hz，1H)，7.33-7.50(m，8H)，6.46(m，1H)，4.76-4.86(m，2H)，4.51(s，2H)，2.98-3.61(m，6H)，1.99(m，1H)，1.78(m，2H)，1.56(m，2H).
Embodiment 96:2-[[1-[2-(2-trifluoromethyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 521 of table 1)
Use 2-trifluoromethyl phenylethyl alcohol, carry out and embodiment 26a, 26b, the same operation of 36c, obtain the title compound (yield 29%) of colorless solid.204～220 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.68(1H，d，J＝7.8)，7.57-7.66(4H，m)，7.38-7.53(3H，m)，6.59(2H，s)，4.49(2H，s)，3.42(2H，d，J＝7.2)，3.00-3.05(2H，m)，2.90-2.99(2H，m)，2.62-2.69(2H，m)，2.14-2.25(2H，m)，1.7-1.9(1H，m)，1.5-1.7(2H，m)，1.1-1.3(2H，m)
Embodiment 97:2-[[1-[2-(1-naphthyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 526 of table 1)
Use the 1-naphthyl ethyl alcohol, carry out and embodiment 26a, 26b, the same operation of 36c, obtain the title compound (yield 60%) of colorless solid.222～229 ℃ of fusing points
1H-NMR(DMSO-d 6)：8.08(1H，d，J＝7.9)，7.91-7.95(1H，m)，7.78-7.80(1H，m)，7.69(1H，d，J＝7.4)，7.41-7.62(7H，m)，6.59(2H，s，fumaric acid)，4.51(2H，s)，3.45(2H，d，J＝7.3)，3.26-3.34(2H，m)，3.15-3.29(2H，m)，2.80-2.87(2H，m)，2.27-2.39(2H，m)，1.7-1.9(1H，m)，1.6-1.7(2H，m)，1.2-1.4(2H，m)
Embodiment 98:2-[[1[2-(2-naphthyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 531 of table 1)
A) 2-[[1[2-(2-naphthyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the 2-naphthyl ethyl alcohol, carry out the operation same, obtain the title compound (yield 77%) of colorless solid with embodiment 26a, 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.73-7.81(3H，m)，7.63(1H，s)，7.21-7.56(6H，m)，4.42(2H，s)，3.52(2H，d，J＝7.2)，2.93-3.07(4H，m)，2.62-2.71(2H，m)，1.99-2.10(2H，m)，1.6-1.9(3H，m)，1.3-1.5(2H，m)
B) 2-[[1[2-(2-naphthyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 98a, carry out the operation same, obtain the title compound (yield 81%) of colorless solid with embodiment 36c.223～233 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.83-7.87(3H，m)，7.73(1H，s)，7.68(1H，d，J＝7.5)，7.56-7.62(2H，m)，7.39-7.49(4H，m)，6.58(2H，s)，4.49(2H，s)，3.43(2H，d，J＝7.2)，3.0-3.2(2H，m)，2.8-3.0(2H，m)，2.7-2.8(2H，m)，2.1-2.3(2H，m)，1.7-1.9(1H，m)，1.5-1.7(2H，m)，1.2-1.4(2H，m)
Embodiment 99:2-[[1-[2-(3-toluyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 536 of table 1)
Use 3-toluyl acetic acid, carry out the operation same, obtain crude product 3-methylbenzene ethanol with embodiment 53b.Carry out and embodiment 26a, 26b, the same operation of 36c with it, obtain the title compound (yield 55%) of colorless solid.214～220 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.68 (1H, d, J=7.5), 7.55-7.61 (2H, m), 7.44-7.52 (1H, m), 7.17 (1H, t, J=7.4), 6.98-7.05 (3H, m), (6.57 2H, s, fumaric acid), 4.49 (2H, s), 3.43 (2H, d, J=7.2), 3.07-3.15 (2H, m), 2.6-2.8 (4H, m), 2.27 (3H, s), 2.1-2.3 (2H, m), 1.7-1.9 (1H, m), and 1.5-1.7 (2H, m), 1.2-1.4 (2H, m)
Embodiment 100:2-[[1-[2-(3-fluorophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 541 of table 1)
Use 3-fluorophenyl acetic acid, carry out the operation same, obtain crude product 3-fluorobenzene ethanol with embodiment 53b.Carry out and embodiment 26a, 26b, the same operation of 36c with it, obtain the title compound (yield 48%) of colorless solid.208～213 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.2), 7.55-7.61 (2H, m), 7.45-7.52 (1H, m), and 7.27-7.35 (1H, m), 7.00-7.12 (3H, m), (6.58 2H, s, fumaric acid), 4.49 (2H, s), 3.42 (2H, d, J=7.2), 3.03-3.10 (2H, m), 2.6-2.9 (4H, m), 2.1-2.3 (2H, m), 1.7-1.9 (1H, m), and 1.5-1.7 (2H, m), 1.1-1.3 (2H, m)
Embodiment 101:2-[[1-[2-(4-p-methoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 546 of table 1)
Use 4-anisole ethanol, carry out and embodiment 26a, 26b, the same operation of 36c, obtain the title compound (yield 68%) of colorless solid.220～227 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.5), 7.56-7.61 (2H, m), 7.45-7.51 (1H, m), 7.13 (2H, d, J=7.8), 6.84 (2H, d, J=7.8), 6.57 (2H, s, fumaric acid), 4.49 (2H, s), 3.71 (3H, s), 3.42 (2H, d, J=7.2), 3.03-3.10 (2H, m), and 2.6-2.8 (4H, m), 2.14-2.26 (2H, m), 1.7-1.9 (1H, m), and 1.5-1.7 (2H, m), 1.2-1.4 (2H, m)
Embodiment 102:2-[[1-[2-(3-p-methoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 551 of table 1)
Use 3-anisole ethanol, carry out and embodiment 26a, 26b, the same operation of 36c, obtain the title compound (yield 43%) of colorless solid.200～206 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.5), 7.56-7.61 (2H, m), 7.45-7.52 (1H, m), 7.19 (1H, t, J=8.0), 6.73-6.82 (3H, m), (6.57 2H, s, fumaric acid), 4.49 (2H, s), 3.73 (3H, s), 3.42 (2H, d, J=7.2), 3.0-3.1 (2H, m), 2.6-2.8 (4H, m), 2.1-2.3 (2H, m), 1.7-1.9 (1H, m), and 1.6-1.7 (2H, m), 1.1-1.3 (2H, m)
Embodiment 103:2-[[1-[2-(2-nitrophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 556 of table 1)
A) 2-[[1-[2-(2-nitrophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use 2-oil of mirbane ethanol, carry out the operation same with embodiment 26a, synthesizing methanesulfonic acid 2-oil of mirbane ethyl ester carries out the operation same with embodiment 26b with it, obtains title compound (52%).
1H-NMR(CDCl 3)：δ7.97(d，J＝8.1Hz，1H)，7.84(d，J＝7.5Hz，1H)，7.39-7.59(m，6H)，4.44(s，2H)，3.57(d，J＝7.5Hz，2H)，3.33-3.42(m，4H)，3.03(m，2H)，2.10(m，1H)，1.63-1.98(m，4H).
B) 2-[[1-[2-(2-nitrophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 103a, carry out the operation same, obtain title compound (yield 84%) with embodiment 1f.248～252 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ11.60(br s，1H)，8.03(d，J＝7.7Hz，1H)，7.68-7.75(m，2H)，7.50-7.62(m，5H)，4.52(s，2H)，2.84-3.59(m，10H)，2.28(m，1H)，1.87(m，2H)，1.62(m，2H).
Embodiment 104:2-[[1-[2-(2-aminophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 561 of table 1)
A) 2-[[1-[2-(2-aminophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
In 10%Pd-C 89mg/MeOH 12mL, add compound 0.500g (1.32mmol) and the HCO that obtains among the embodiment 103a 2NH 4208mg (3.30mmol)/H 2O 3mL refluxed after 1.5 hours, filtered Pd, concentrated filtrate.To wherein adding entry, use dichloromethane extraction 3 times, with the organic layer Na that merges 2SO 4Dry.The filtering siccative after concentrating, obtains title compound (yield 93%).
1H-NMR(CDCl 3)：δ7.85(d，J＝7.3Hz，1H)，7.42-7.53(m，3H)，6.97-7.04(m，2H)，6.65-6.70(m，2H)，4.40(s，2H)，3.51(d，J＝7.2Hz，2H)，3.02(brd，J＝11.6Hz，2H)，2.70(dd，J＝7.1，6.5Hz，2H)，2.56(dd，J＝7.1，6.5Hz，2H)，2.00(dt，J＝11.6，2.0Hz，2H)，1.81(m，1H)，1.71(br d，J＝12Hz，2H)，1.40(dq，J＝12，3Hz，2H).
B) 2-[[1-[2-(2-aminophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 104a, carry out the operation same, obtain title compound (yield 93%) with embodiment 1f.239～243 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.69(d，J＝7.2Hz，1H)，7.61(m，1H)，7.49(m，1H)，7.16-7.32(m，4H)，4.52(s，2H)，2.87-3.75(m，10H)，2.04(m，1H)，1.84(m，2H)，1.59(m，2H).
Embodiment 105:2-[[1-[2-(2-acetylamino phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 566 of table 1)
A) 2-[[1-[2-(2-acetylamino phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
The compound 246mg (0.704mmol) that obtains among the embodiment 104a is dissolved among the pyridine 1mL, adds acetic anhydride 144mg (1.41mmol), be heated to 60 ℃.After 1 hour, reaction solution dilutes with saturated aqueous common salt, uses dichloromethane extraction 3 times, with the organic layer Na that merges 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (methylene chloride), obtain title compound (yield 47%).
1H-NMR(CDCl 3)：δ10.01(br s，1H)，7.93(d，J＝7.8Hz，1H)，7.85(d，J＝7.2Hz，1H)，7.43-7.55(m，3H)，7.22(m，1H)，6.95-7.09(m，2H)，4.41(s，2H)，3.54(d，J＝7.2Hz，2H)，3.06(br d，J＝12Hz，2H)，2.81(m，2H)，2.66(m，2H)，2.23(s，3H)，2.18(m，2H)，1.91(m，1H)，1.78(m，2H)，1.50(m，2H).
B) 2-[[1-[2-(2-acetylamino phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 105a, carry out the operation same, obtain title compound (yield 77%) with embodiment 1f.134 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.36(br s，1H)，9.53(br s，1H)，7.67(d，J＝7.8Hz，1H)，7.59(m，2H)，7.15-7.35(m，4H)，4.50(s，2H)，2.81-3.58(m，10H)，2.09(s，3H)，2.00(m，1H)，1.80(m，2H)，1.56(m，2H).
Embodiment 106:2-[[1-[2-(2-methylamino phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone 1/4 fumarate (compound 571 of table 1)
A) 2-[[1-[2-(2-methylamino phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
In acetic anhydride 0.241g (2.36mmol), splash into formic acid 0.133g (2.83mmol), be heated to 50 ℃.After 2 hours, reaction solution is cooled to 0 ℃ with 1mL THF dilution, splashes into compound 411mg (the 1.18mmol)/3mL THF solution that obtains among the embodiment 104a.Stir after 30 minutes, add saturated aqueous common salt, use dichloromethane extraction 4 times, with the organic layer Na that merges 2SO 4Dry.
The filtering siccative after concentrating, is dissolved among the THF 1mL, is cooled to 0 ℃, splashes into BH 3SMe 290 μ l (0.952mmol).Be warming up to room temperature, stir after 3 hours, be cooled to 0 ℃, splash into methyl alcohol 0.5ml.Further add 1N NaOH aqueous solution 3mL, stir after 30 minutes, add saturated aqueous common salt, use dichloromethane extraction 4 times, the organic layer Na that merges 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (methylene chloride), obtain title compound (yield 72%)
1H-NMR(CDCl 3)：δ7.85(d，J＝7.5Hz，1H)，7.45-7.55(m，3H)，7.18(m，1H)，6.97(m，1H)，6.60-6.65(m，2H)，4.44(s，2H)，3.57(d，J＝6.9Hz，2H)，3.21(br d，J＝12Hz，2H)，3.07(m，2H)，2.88(s，3H)，2.78(m，2H)，2.42(br t，J＝12Hz，2H)，2.16(m，2H)，2.02(m，1H)，1.64(m，2H).
B) 2-[[1-[2-(2-methylamino phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone 1/4 fumarate
Use the compound that obtains among the embodiment 106a, carry out the operation same, obtain title compound (yield 77%) with embodiment 40f.155 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.69(d，J＝7.5Hz，1H)，7.60(m，2H)，7.49(m，1H)，7.07(t，J＝7.7Hz，1H)，6.95(d，J＝7.2Hz，1H)，6.62(s，0.5H)，6.50-6.58(m，2H)，4.50(s，2H)，3.48(d，J＝6.1Hz，2H)，2.92-3.02(m，4H)，2.78(m，2H)，2.72(s，3H)，2.63(br t，J＝11Hz，2H)，1.79-1.89(m，3H)，1.52(m，2H).
Embodiment 107:2-[[1-[2-(4-fluorobenzene sulfenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 706 of table 1)
A) 2-[[1-[2-(4-fluorobenzene sulfenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With 4-fluorobenzene mercaptan (0.50ml, 4.69mmol) and ethylene bromohyrin (0.345ml 4.87mmol) is dissolved in the tetrahydrofuran (THF) (12ml).(4.8ml, 4.8mmol) The was 80 ℃ of following heated and stirred 80 minutes to wherein adding 1 Equivalent Hydrogen aqueous solution of sodium oxide.Reaction solution with dilute sodium hydroxide aqueous solution, water, saturated common salt water washing, is used dried over mgso with vinyl acetic monomer-hexane mixed solvent dilution.Filter insolubles, decompression is concentrated filtrate down, obtains crude product 2-(4-fluorophenyl sulfo-) ethanol.Carry out the operation same with it, obtain crude product 2-(4-fluorophenyl sulfo-) ethanol methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 64%) of colorless solid with embodiment 26b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5)，7.40-7.55(3H，m)，7.31-7.39(2H，m)，6.98(2H，t，J＝8.9)，4.39(2H，s)，3.49(2H，d，J＝7.2)，2.95-3.02(2H，m)，2.85-2.94(2H，m)，2.54-2.61(2H，m)，1.94-2.04(2H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
B) 2-[[1-[2-(4-fluorobenzene sulfenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 107a, carry out the operation same, obtain the title compound (yield 86%) of colorless solid with embodiment 1f.185～192 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.55(1H，brs，HCl)，7.68(1H，d，J＝7.5)，7.59-7.62(2H，m)，7.46-7.52(3H，m)，7.18-7.25(2H，m)，4.50(2H，s)，3.1-3.7(8H，m)，2.7-2.9(2H，m)，1.7-2.0(3H，m)，1.4-1.6(2H，m)
Embodiment 108:2-[[1-[3-(4-fluorobenzene sulfenyl) propyl group] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 711 of table 1)
A) 3-(4-fluorobenzene sulfenyl) propyl alcohol
(788mg, 6.15mmol) (0.535ml 6.16mmol) is dissolved in the tetrahydrofuran (THF) (20ml) with the 3-bromopropyl alcohol with 4-fluorobenzene mercaptan.To wherein add 1 Equivalent Hydrogen aqueous solution of sodium oxide (6.2ml, 6.2mmol), 80 ℃ of following heated and stirred 3 hours.Reaction solution with dilute sodium hydroxide aqueous solution, water, saturated common salt water washing, is used dried over mgso with vinyl acetic monomer-hexane mixed solvent dilution.Filter insolubles, decompression is concentrated filtrate down.The oily matter that obtains is refining with silica gel column chromatography (vinyl acetic monomer-hexane), the title compound 592mg (yield 52%) of acquisition colorless oil.
1H-NMR(CDCl 3)：7.33-7.39(2H，m)，6.97-7.03(2H，m)，3.77(2H，t，J＝6.0)，2.99(2H，t，J＝7.3)，1.80-1.91(2H，m)，1.49(1H，brs，OH)
B) 2-[[1-[3-(4-fluorobenzene sulfenyl) propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 108a, carry out the operation same, obtain crude product 3-(4-fluorophenyl sulfo-) propyl alcohol methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 86%) of faint yellow solid with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.41-7.55(3H，m)，7.30-7.37(2H，m)，6.98(2H，t，J＝8.6)，4.40(2H，s)，3.40(2H，d，J＝7.3)，2.83-2.92(4H，m)，2.41(2H，t，J＝7.5)，1.86-1.96(2H，m)，1.5-1.8(5H，m)，1.2-1.4(2H，m)
C) 2-[[1-[3-(4-fluorobenzene sulfenyl) propyl group] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 108b, carry out the operation same, obtain the title compound (yield 52%) of colorless solid with embodiment 1f.162～164 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.8-10.6(1H，brs，HCl)，7.68(1H，d，J＝7.5)，7.60-7.62(2H，m)，7.42-7.52(3H，m)，7.17-7.24(2H，m)，4.50(2H，s)，2.9-3.7(8H，m)，2.6-2.g(2H，m)，1.8-2.0(3H，m)，1.6-1.8(2H，m)，1.4-1.6(2H，m)
Embodiment 109:2-[[1-[2-(thiophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 726 of table 1)
Use thiophenol, carry out the operation same, obtain crude product 2-[[1-[2-(phenyl sulfo-) ethyl with embodiment 107a] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound (yield 62%) of colorless solid with embodiment 36c.188～192 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.55-7.60(2H，m)，7.45-7.52(1H，m)，7.27-7.35(4H，m)，7.14-7.20(1H，m)，6.60(2H，s，fumaric acid)，4.47(2H，s)，3.40(2H，d，J＝7.2)，3.06-3.18(2H，m)，2.88-2.95(2H，m)，2.5-2.6(2H，m)，1.9-2.1(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 110:2-[[1-[2-(2-anisole sulfenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 731 of table 1)
Use 2-anisole mercaptan, carry out the operation same, obtain crude product 2-[[1-[2-(2-p-methoxy-phenyl sulfo-) ethyl with embodiment 107a] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound (yield 53%) of colorless solid with embodiment 36c.166～169 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5)，7.55-7.60(2H，m)，7.45-7.52(1H，m)，7.14-7.25(2H，m)，6.90-6.99(2H，m)，6.60(2H，s，fumaric acid)，4.48(2H，s)，3.80(3H，s)，3.41(2H，d，J＝7.3)，2.99-3.06(2H，m)，2.91-2.98(2H，m)，2.55-2.64(2H，m)，2.01-2.11(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 111:2-[[1-[2-(3-anisole sulfenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 736 of table 1)
Use 3-anisole mercaptan, carry out the operation same, obtain crude product 2-[[1-[2-(3-p-methoxy-phenyl sulfo-) ethyl with embodiment 107a] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound (yield 40%) of colorless solid with embodiment 36c.156～159 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.4)，7.56-7.61(2H，m)，7.45-7.52(1H，m)，7.21(1H，t，J＝7.9)，6.84-6.91(2H，m)，6.71-6.77(1H，m)，6.61(2H，s，fumaricacid)，4.48(2H，s)，3.74(3H，s)，3.40(2H，d，J＝7.3)，3.07-3.15(2H，m)，2.90-2.97(2H，m)，2.56-2.63(2H，m)，2.02-2.09(2H，m)，1.6-1.8(1H，m)，1.5-1.6(2H，m)，1.1-1.3(2H，m)
Embodiment 112:2-[[1-[2-(2-fluorobenzene sulfenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 716 of table 1)
Use 2-fluorobenzene mercaptan, carry out the operation same, obtain crude product 2-[[1-[2-(2-fluorophenyl sulfo-) ethyl with embodiment 107a] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound (yield 46%) of colorless solid with embodiment 36c.187～189 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.2), 7.55-7.60 (2H, m), 7.41-7.52 (2H, m), and 7.14-7.28 (3H, m), 6.61 (2H, s, fumaric acid), 4.47 (2H, s), 3.39 (2H, d, J=7.2), and 3.05-3.13 (2H, m), 2.86-2.92 (2H, m), 2.54-2.63 (2H, m), 1.9-2.1 (2H, m), 1.6-1.8 (1H, m), and 1.5-1.6 (2H, m), 1.1-1.3 (2H, m)
Embodiment 113:2-[[1-[2-(3-fluorobenzene sulfenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 721 of table 1)
Use 3-fluorobenzene mercaptan, carry out the operation same, obtain crude product 2-[[1-[2-(3-fluorophenyl sulfo-) ethyl with embodiment 107a] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound (yield 48%) of colorless solid with embodiment 36c.194～198 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.4), 7.55-7.61 (2H, m), 7.45-7.45-7.52 (1H, m), and 7.28-7.36 (1H, m), 7.11-7.22 (2H, m), 6.94-7.02 (1H, m), 6.60 (2H, s, fumaric acid), 4.48 (2H, s), 3.40 (2H, d, J=7.2), 3.12-3.19 (2H, m), 2.90-2.96 (2H, m), and 2.56-2.64 (2H, m), 1.97-2.08 (2H, m), 1.6-1.8 (1H, m), and 1.5-1.6 (2H, m), 1.1-1.3 (2H, m)
Embodiment 114:2-[[1-(2-phenoxy group ethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 611 of table 1)
A) 1-(4-methylbenzene) sulfonyloxy-2-phenoxy group ethane
With the 2-phenoxyethyl alcohol (500mg 3.62mmol) is dissolved in the methylene dichloride (7ml), add the chlorination tolysulfonyl (690mg, 3.62mmol) and triethylamine (0.51ml 3.62mmol), at room temperature stirred 15 hours.Reaction solution dilutes with methylene dichloride, after washing with water, uses dried over mgso.After insolubles filtered, filtrate was removed in underpressure distillation, obtained title compound 1.08g (quantitative yield).
1H-NMR(CDCl 3)：7.83(2H，d，J＝1.8Hz)，7.34(2H，d，J＝8.4Hz)，7.28-7.23(2H，m)，6.98-6.93(1H，m)，6.78(2H，d，J＝7.8Hz)，4.37(2H，t，J＝4.8Hz)，4.14(2H，t，J＝5.0Hz)，2.44(3H，s).
B) 2-[[1-(2-phenoxy group ethyl) piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound (547mg that obtains among the embodiment 114a, 1.87mmol) be dissolved in the dimethyl formamide (3ml), add the compound that obtains among the embodiment 1d (500mg, 1.87mmol) and salt of wormwood (517mg, 3.74mmol), 60 ℃ of following heated and stirred 7 hours.With reaction solution put cold after, in reaction solution, add entry (10ml), behind ethyl acetate extraction, dried over sodium sulfate is used in water, saturated common salt water washing.Filter insolubles, filtrate is removed in underpressure distillation, and the solid of acquisition filters and collects after dry-cleaning with ether-hexane, obtains the crude product (171mg) of title compound.The crude product that obtains is directly used in following reaction without making with extra care.
C) 2-[[1-(2-phenoxy group ethyl) piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (170mg) that obtains among the embodiment 114b, carry out the reaction same, obtain the title compound 170mg (yield 19%, 2 step) of colorless solid with embodiment 36c.178～181 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5Hz)，7.59(2H，d，J＝4.2Hz)，7.51-7.47(1H，m)，6.95-6.90(3H，m)，6.59(2H，s)，4.48(2H，s)，4.11(2H，brt，J＝5.7Hz)，3.42(2H，brd，J＝10.2Hz)，2.85(2H，brt，J＝5.4hz)，2.23(2H，brdd，J＝11.3，11.3Hz)，1.80-1.75(1H，m)，1.61(2H，brd，J＝12.9Hz)，1.28(2H，brdd，J＝23.0，10.2Hz).
Embodiment 115:2-[[1-[2-(4-chlorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 626 of table 1)
A) 1-bromine 2-(4-chlorophenoxy) ethane
With the 4-chlorophenol (500mg, 3.89mg), ethylene bromohyrin (0.28ml, 3.89mmol), triphenylphosphine (1.02g, 3.89mmol) be dissolved in the tetrahydrofuran (THF) (8ml), (0.84ml 3.89mmol), at room temperature stirred 3 hours to splash into the diisopropyl azo-2-carboxylic acid.After the solvent of reaction solution concentrated, separate out solid, filter the back underpressure distillation and remove filtrate, the crude product (1.18g) of acquisition title compound with ether-hexane.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(4-chlorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
The compound (500mg) that obtains among the embodiment 115a is dissolved in the dimethyl formamide (2ml), add the compound that obtains among the embodiment 1d (440mg, 1.65mmol), salt of wormwood (456mg, 3.30mmol), sodium iodide (247mg, 1.65mmol), 60 ℃ of following heated and stirred 17 hours.With reaction solution put cold after, with vinyl acetic monomer dilution, dried over sodium sulfate is used in water, saturated common salt water washing.After filtering insolubles, filtrate is removed in underpressure distillation, and the crude product that obtains is refining with silica gel column chromatography (methyl alcohol-methylene dichloride), obtains filbert solid title compound 273mg (18%, 2 step).
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.4Hz)，7.56-7.42(3H，m)，7.23-7.19(2H，m)，6.84-6.80(2H，m)，4.40(2H，s)，4.05(2H，t，J＝5.8Hz)，3.51(2H，d，J＝7.3Hz)，2.98(2H，brd，J＝11.8Hz)，2.77(2H，t，J＝5.9Hz)，2.10(2H，ddd，J＝2.3，11.6，11.6Hz)，1.84-1.68(3H，m)，1.45-1.40(2H，m)
C) 2-[[1-[2-(4-chlorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
(270mg 0.70mmol), carries out the reaction same with embodiment 36c, obtains the title compound 272mg (yield 78%) of colorless solid to use the compound that obtains among the embodiment 115b.189～192 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.4Hz)，7.59(2H，d，J＝1.4Hz)，7.58-7.46(1H，m)，7.31(1H，dd，J＝7.5，2.1Hz)，6.97(2H，dd，J＝6.7，2.1Hz)，6.59(2H，s)，4.48(2H，s)，4.10(2H，t，J＝5.7Hz)，3.41(2H，d，J＝7.3Hz)，3.00(2H，brd，J＝11.7Hz)，2.80(2H，t，J＝5.8Hz)，2.17(2H，dd，J＝10.7，10.7Hz)，1.79(1H，m)，1.60(2H，brd，J＝12.4Hz)，1.33-1.21(2H.m).
Embodiment 116:2-[[1-[2-(2-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 631 of table 1)
A) 1-bromine 2-(2-methoxyl group phenoxy group) ethane
(186mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (551mg) of title compound to use the 2-methoxyphenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(2-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (551mg) that obtains among the embodiment 116a, carry out the reaction same, obtain the title compound 119mg (yield 21%, 2 step) of brown oil with embodiment 115b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5Hz)，7.56-7.42(3H，m)，6.92-6.87(4H，m)，4.41(2H，s)，4.14(2H，t，J＝6.2Hz)，3.85(3H，s)，3.51(2H，d，J＝7.2Hz)，3.02(2H，brd，J＝11.7Hz)，2.83(2H，t，J＝6.2Hz)，2.15-2.07(2H，m)，1.87-1.69(3H，m)，1.51-1.37(2H，m).
C) 2-[[1-[2-(2-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
(119mg 0.32mmol), carries out the reaction same with embodiment 36c, obtains the title compound 108mg (yield 69%) of colorless solid to use the compound that obtains among the embodiment 116b.188～191 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5Hz)，7.59-7.50(3H，m)，7.00-6.84(4H，m)，6.59(2H，s)，4.48(2H，s)，4.09(2H，t，J＝5.7Hz)，3.74(3H，s)，3.41(2H，d，J＝7.2Hz)，3.05(2H，brd，J＝11.1Hz)，2.83(2H，brs)，2.22(2H，brdd，J＝11.0，11.0Hz)，1.78-1.77(1H，m)，1.62(2H，brd，J＝12.0Hz)，1.28(2H，brdd，J＝21.8，11.4Hz).
Embodiment 117:2-[[1-[2-(2-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 616 of table 1)
A) 1-bromine 2-(2-fluorophenoxy) ethane
(168mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (418mg) of title compound to use the 2-fluorophenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(2-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (418mg) that obtains among the embodiment 117a, carry out the reaction same, obtain the title compound 240mg (yield 43%, 2 step) of brown oil with embodiment 115b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.2Hz)，7.53-7.42(3H，m)，7.07-6.96(4H，m)，4.41(2H，s)，4.16(2H，t，J＝6.0Hz)，3.51(2H，d，J＝7.2Hz)，3.01(2H，brd，J＝11.7Hz)，2.82(2H，t，J＝6.0Hz)，2.13(2H，ddd，J＝23.3，11.6，11.6Hz)，1.84-1.68(3H，m)，1.49-1.40(2H，m).
C) 2-[[1-[2-(2-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (240mg) that obtains among the embodiment 117b, carry out the reaction same, obtain the title compound 108mg (yield 78%) of colorless solid with embodiment 36c.168～171 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5Hz)，7.58(2H，brs)，7.50-7.47(1H，m)，7.22-7.11(3H，m)，6.94-6.92(1H，m)，6.60(2H，s)，4.48(2H，s)，4.17(2H，t，J＝5.6Hz)，3.40(2H，d，J＝7.2Hz)，3.00(2H，brd，J＝11.1Hz)，2.81(2H，brdd，J＝5.6，5.6Hz)，2.17(2H，brdd，J＝10.7，10.7Hz)，1.76-1.73(1H，m)，1.62(2H，brd，J＝12.0Hz)，1.25(2H，brdd，J＝22.4，10.6Hz).
Embodiment 118:2-[[1-[2-(3-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 621 of table 1)
A) 1-bromine 2-(3-fluorophenoxy) ethane
(500mg 4.46mmol), carries out the reaction same with embodiment 115a, obtains the crude product (1.26g) of title compound to use the 3-fluorophenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(3-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (1.26g) that obtains among the embodiment 118a, carry out the reaction same, obtain the title compound 823mg (yield 50%, 2 step) of brown oil with embodiment 115b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.2Hz)，7.53-7.42(3H，m)，7.21-7.16(1H，m)，6.69-6.59(3H，m)，4.41(2H，s)，4.07(2H，t，J＝5.9Hz)，3.51(2H，d，J＝7.2Hz)，2.99(2H，brd，J＝12.0Hz)，2.78(2H，t，J＝6.0Hz)，2.11(2H，ddd，J＝2.5，11.6，11.6Hz)，1.82-1.68(3H，m)，1.49-1.40(2H，m).
C) 2-[[1-[2-(3-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (823mg) that obtains among the embodiment 118b, carry out the reaction same, obtain the title compound 720mg (yield 67%) of colorless solid with embodiment 36c.193～194 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.4Hz)，7.60-7.58(2H，m)，7.51-7.48(1H，m)，7.34-7.31(1H，m)，6.84-6.75(3H，m)，6.59(2H，s)，4.48(2H，s)，4.12(2H，t，J＝5.7Hz)，3.41(2H，d，J＝7.3Hz)，3.02(2H，brd，J＝11.7Hz)，2.81(2H，brdd，J＝5.7，5.7Hz)，2.19(2H，brdd，J＝10.5，10.5Hz)，1.79-1.74(1H，m)，1.61(2H，brd，J＝12.0Hz)，1.32-1.20(2H，m).
Embodiment 119:2-[[1-[2-(4-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 656 of table 1)
A) 1-bromine 2-(4-methylphenoxy) ethane
(162mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (458mg) of title compound to use the 4-methylphenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(4-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (458mg) that obtains among the embodiment 119a, carry out the reaction same, obtain the title compound 210mg (yield 38%, 2 step) of brown oil with embodiment 115b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝6.9Hz)，7.55-7.42(3H，m)，7.06(2H，d，J＝8.4Hz)，6.81-6.77(2H，m)，4.40(2H，s)，4.06(2H，t，J＝6.0Hz)，3.50(2H，d，J＝7.2Hz)，3.00(2H，brd，J＝11.7Hz)，2.77(2H，t，J＝6.0Hz)，2.27(3H，s)，2.10(2H，ddd，J＝2.3，11.6，11.6Hz)，1.84-1.70(3H，m)，1.49-1.40(2H，m).
C) 2-[[1-[2-(4-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (210mg) that obtains among the embodiment 119b, carry out the reaction same, obtain the title compound 220mg (yield 79%) of colorless solid with embodiment 36c.183～185 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.6Hz)，7.62-7.58(2H，m)，7.52-7.45(1H，m)，7.07(2H，d，J＝8.3Hz)，6.82(2H，d，J＝8.4Hz)，6.59(2H，s)，4.48(2H，s)，4.05(2H，t，J＝5.7Hz)，3.41(2H，d，J＝7.2Hz)，3.00(2H，brd，J＝11.6Hz)，2.78(2H，t，J＝5.7Hz)，2.22-2.09(5H，m)，1.79-1.73(1H，m)，1.61(2H，brd，J＝13.3Hz)，1.26(2H，brdd，J＝21.4，11.4Hz).
Embodiment 120:2-[[1-[2-(3-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 636 of table 1)
A) 1-bromine 2-(3-methoxyl group phenoxy group) ethane
(186mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (953mg) of title compound to use the 4-methoxyphenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(3-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (953mg) that obtains among the embodiment 120a, carry out the reaction same, obtain the title compound 192mg (yield 34%, 2 step) of brown oil with embodiment 115b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.2Hz)，7.55-7.42(3H，m)，7.16(1H，dd，J＝8.0，8.0Hz)，6.51-6.46(3H，m)，4.41(2H，s)，4.08(2H，t，J＝6.0Hz)，3.78(3H，s)，3.51(2H，d，J＝7.2Hz)，3.00(2H，brd，J＝11.7Hz)，2.79(2H，t，J＝6.0Hz)，2.16-2.08(2H，m)，1.83-1.68(3H，m)，1.50-1.41(2H，m).
C) 2-[[1-[2-(3-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (190mg) that obtains among the embodiment 120b, carry out the reaction same, obtain the title compound 200mg (yield 81%) of colorless solid with embodiment 36c.173～174 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.5Hz)，7.62-7.58(2H，m)，7.52-7.45(1H，m)，7.17(1H，dd，J＝8.3，8.0Hz)，6.59(2H，s)，6.53-6.49(3H，m)，4.48(2H，s)，4.09(2H，t，J＝5.4Hz)，3.72(3H，s)，3.41(2H，d，J＝7.2Hz)，3.03(2H，brd，J＝11.2Hz)，，2.82(2H，brs)，2.21(2H，brdd，J＝11.4，11.4Hz)，1.78-1.77(1H，m)，1.62(2H，brd，J＝12.5Hz)，1.28(2H，brdd，J＝22.0，11.0Hz).
Embodiment 121:2-[[1-[2-(3-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 651 of table 1)
A) 1-bromine 2-(3-methylphenoxy) ethane
(162mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (410mg) of title compound to use the 3-methylphenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(3-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (410mg) that obtains among the embodiment 121a, carry out the reaction same, obtain the title compound 213mg (yield 39%, 2 step) of brown oil with embodiment 115b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5Hz)，7.55-7.42(3H，m)，7.14(1H，dd，J＝7.7，7.7Hz)，6.76-6.69(3H，m)，4.40(2H，s)，4.08(2H，t，J＝5.9Hz)，3.51(2H，d，J＝6.9Hz)，3.00(2H，brd，J＝11.7Hz)，2.79(2H，t，J＝5.9Hz)，2.31(3H，s)，2.12(2H，brdd，J＝10.5，10.5Hz)，1.82-1.69(3H，m)，1.49-1.26(2H，m).
C) 2-[[1-[2-(3-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (210mg) that obtains among the embodiment 121b, carry out the reaction same, obtain the title compound 252mg (yield 91%) of colorless solid with embodiment 36c.202～203 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.4Hz)，7.59-7.58(2H，m)，7.50-7.45(1H，m)，7.15(1H，dd，J＝7.8，7.8Hz)，6.75-6.71(3H，m)，6.59(2H，s)，4.48(2H，s)，4.09(2H，t，J＝5.5Hz)，3.41(2H，d，J＝7.3Hz)，3.04(2H，brd，J＝11.3Hz)，2.83(2H，t，J＝5.0Hz)，2.26-2.19(5H，m)，1.78(1H，brs)，1.62(2H，brd，J＝12.7Hz)，1.28(2H，brdd，J＝21.9，10.7Hz).
Embodiment 122:2-[[1-[2-(4-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 641 of table 1)
A) 1-bromine 2-(4-methoxyl group phenoxy group) ethane
(186mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (347mg) of title compound to use the 4-methoxyphenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(4-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (347mg) that obtains among the embodiment 122a, carry out the reaction same, obtain the title compound 274mg (yield 48%, 2 step) of brown oil with embodiment 115b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.2Hz)，7.56-7.42(3H，m)，6.82-6.78(4H，m)，4.41(2H，s)，4.05(2H，t，J＝5.9Hz)，3.76(3H，s)，3.51(2H，d，J＝7.2Hz)，3.00(2H，brd，J＝12.0Hz)，2.77(2H，t，J＝6.0Hz)，2.11(2H，ddd，J＝2.3，11.6，11.6Hz)，1.82-1.68(3H，m)，1.51-1.41(2H，m).
C) 2-[[1-[2-(4-methoxyl group phenoxy group) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (270mg) that obtains among the embodiment 122b, carry out the reaction same, obtain the title compound 232mg (yield 82%) of colorless solid with embodiment 36c.165～168 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.3Hz)，7.59-7.58(2H，m)，7.52-7.45(1H，m)，6.89-6.82(4H，m)，6.59(2H，s)，4.48(2H，s)，4.04(2H，t，J＝5.7Hz)，3.41(2H，d，J＝7.3Hz)，3.03(2H，brd，J＝11.6Hz)，2.80(2H，t，J＝5.7Hz)，2.21(2H，brdd，J＝10，7，10.7Hz)，1.80-1.79(1H，m)，1.61(2H，brd，J＝11.6Hz)，1.33-1.18(2H，m).
Embodiment 123:2-[[1-[2-(2-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 646 of table 1)
A) 1-bromine 2-(2-methylphenoxy) ethane
(162mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (334mg) of title compound to use the 2-methylphenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(2-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (334mg) that obtains among the embodiment 123a, carry out the reaction same, obtain the crude product 485mg of the title compound of brown oil with embodiment 115b.The crude product that obtains is directly used in following reaction without making with extra care.
C) 2-[[1-[2-(2-methylphenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (485mg) that obtains among the embodiment 123b, carry out the reaction same, obtain the title compound 89mg (yield 14%, 3 step) of colorless solid with embodiment 36c.214～218 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.2Hz)，7.59-7.58(2H，m)，7.52-7.45(1H，m)，7.16-7.11(2H，m)，6.92(1H，d，J＝8.1Hz)，6.82(1H，dd，J＝7.5，7.5Hz))，6.59(2H，s)，4.48(2H，s)，4.10(2H，t，J＝5.6Hz)，3.41(2H，d，J＝7.2Hz)，3.03(2H，brd，J＝12.0Hz)，2.85(2H，brs)，2.23(2H，brdd，J＝11.0，11.0Hz)，2.13(s，3H)，1.77(1H，brs)，1.61(2H，brd，J＝12.3Hz)，1.32-1.24(2H，m).
Embodiment 124:2-[[1-[2-(4-4-trifluoromethylphenopendant) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 661 of table 1)
A) 1-bromine 2-(4-4-trifluoromethylphenopendant) ethane
(243mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (519mg) of title compound to use the 4-trifloro methyl phenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(4-4-trifluoromethylphenopendant) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (519mg) that obtains among the embodiment 124a, carry out the reaction same, obtain title compound 150mg (yield 19%, 2 step) with embodiment 115b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.2Hz)，7.56-7.42(5H，m)，6.95(2H，d，J＝8.7Hz)，4.41(2H，s)，4.13(2H，t，J＝5.9Hz)，3.51(2H，d，J＝6.9Hz)，3.00(2H，brd，J＝11.4Hz)，2.81(2H，t，J＝5.9Hz)，2.17-2.09(2H，m)，1.85-1.63(3H，m)，1.50-1.38(2H，m).
C) 2-[[1-[2-(4-4-trifluoromethylphenopendant) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (150mg) that obtains among the embodiment 124b, carry out the reaction same, obtain the title compound 171mg (yield 89%) of colorless solid with embodiment 36c.198～199 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.68-7.56(5H，m)，7.52-7.45(1H，m)，7.12(2H，d，J＝8.6Hz)，6.60(2H，s)，4.48(2H，s)，4.18(2H，t，J＝5.7Hz)，3.41(2H，d，J＝7.2Hz)，2.98(2H，brd，J＝11.6Hz)，2.79(2H，t，J＝5.7Hz)，2.13(2H，brdd，J＝11，7，11.7Hz)，1.79-1.72(1H，m)，1.60(2H，brd，J＝12.3Hz)，1.38-1.18(2H，m).
Embodiment 125:2-[[1-[2-(4-Trifluoromethyl phenyl ether oxygen base) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 666 of table 1)
A) 1-bromine 2-(4-Trifluoromethyl phenyl ether oxygen base) ethane
(267mg 1.5mmol), carries out the reaction same with embodiment 115a, obtains the crude product (598mg) of title compound to use the 4-trifluoro-methoxy-phenol.The crude product that obtains is directly used in following reaction without making with extra care.
B) 2-[[1-[2-(4-4-trifluoromethylphenopendant) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound (598mg) that obtains among the embodiment 125a, carry out the reaction same, obtain the crude product 589mg of title compound with embodiment 115b.The crude product that obtains is directly used in following reaction without making with extra care.
C) 2-[[1-[2-(4-4-trifluoromethylphenopendant) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound (589mg) that obtains among the embodiment 125b, carry out the reaction same, obtain the title compound 304mg (yield 55%, 3 step) of colorless solid with embodiment 36c.181～183 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.67(1H，d，J＝7.3Hz)，7.59-7.58(2H，m)，7.50-7.45(1H，m)，7.28(2H，d，J＝8.9Hz)，7.06-7.00(2H，m)，6.60(2H，s)，4.48(2H，s)，4.11(2H，t，J＝5.7Hz)，3.41(2H，d，J＝7.2Hz)，2.98(2H，brd，J＝11.7Hz)，2.78(2H，t，J＝5.7Hz)，2.18-2.09(2H，m)，1.80-1.72(1H，m)，1.60(2H，m)，1.30-1.19(2H，m).
Embodiment 126:2-[[1-[2-(1,3-benzo dioxole-5-base oxygen base) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 671 of table 1)
Use 3,4-methylene-dioxy phenol carries out and embodiment 115a, the same operation of embodiment 36c, obtains the title compound (yield 52%) of colorless solid.220～232 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.5), 7.55-7.60 (2H, m), 7.45-7.52 (1H, m), 6.79 (1H, d, J=8.4), 6.62 (1H, d, J=2.4), 6.59 (2H, s, fumaric acid), 6.36 (1H, dd, J=2.4,8.4), 5.94 (2H, s), 4.48 (2H, s), 3.98-4.04 (2H, m), 3.41 (2H, d, J=7.2), and 2.94-3.01 (2H, m), 2.71-2.77 (2H, m), 2.08-2.19 (2H, m), 1.6-1.8 (1H, m), 1.5-1.6 (2H, m), 1.1-1.3 (2H, m)
Embodiment 127:2-[[1-[2-(2,3-dihydro-1H-indenes-5-base oxygen base) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 676 of table 1)
Use 5-indanol (イ Application ダ ノ-Le), carry out and embodiment 115a, the same operation of embodiment 36c, obtain the title compound (yield 22%) of colorless solid.181～185 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.2), 7.55-7.60 (2H, m), 7.45-7.52 (1H, m), 7.08 (1H, d, J=8.4), 6.80 (1H, d, J=2.1), 6.67 (1H, dd, J=2.1,8.4), 6.59 (2H, s, fumaric acid), 4.49 (2H, s), 4.02-4.08 (2H, m), 3.41 (2H, d, J=7.2), 2.96-3.03 (2H, m), and 2.72-2.84 (6H, m), 2.12-2.22 (2H, m), 1.93-2.04 (2H, m), 1.6-1.8 (1H, m), 1.5-1.6 (2H, m), 1.1-1.3 (2H, m)
Embodiment 128:2-[[1-[2-(5,6,7,8-naphthane-2-base oxygen base) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 681 of table 1)
Use 5,6,7, the 8-tetralol carries out and embodiment 115a, the same operation of embodiment 36c, obtains the title compound (yield 19%) of colorless solid.186～190 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.2), 7.55-7.60 (2H, m), 7.45-7.52 (1H, m), 6.92 (1H, d, J=8.1), 6.60-6.67 (2H, m), (6.59 2H, s, fumaric acid), 4.48 (2H, s), 3.99-4.06 (2H, m), 3.41 (2H, d, J=7.2), 2.95-3.02 (2H, m), 2.72-2.79 (2H, m), 2.60-2.69 (4H, m), 2.10-2.20 (2H, m), and 1.55-1.80 (7H, m), 1.1-1.3 (2H, m)
Embodiment 129:2-[[1-[2-(5,6,7,8-naphthane-1-base oxygen base) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 686 of table 1)
Use 5,6,7,8-tetrahydrochysene-1-naphthols carries out and embodiment 115a, the same operation of embodiment 36c, obtains the title compound (yield 13%) of colorless solid.196～203 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.5), 7.55-7.60 (2H, m), 7.45-7.52 (1H, m), 6.97-7.05 (1H, m), 6.70 (1H, d, J=8.1), 6.64 (1H, d, J=7.5), 6.59 (2H, s, fumaric acid), 4.48 (2H, s), 4.03-4.09 (2H, m), 3.41 (2H, d, J=7.2), 2.98-3.05 (2H, m), 2.80-2.85 (2H, m), 2.62-2.70 (2H, m), 2.50-2.55 (2H, m), 2.1-2.3 (2H, m), 1.5-1.8 (7H, m), 1.1-1.3 (2H, m)
Embodiment 130:2-[[1-[2-[methyl (4-fluorophenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 295 of table 1)
A) N-(4-fluorophenyl) t-butyl carbamate
In 4-fluoroaniline 2.00g (18.0mmol)/15mL dichloromethane solution, add (Boc) 2The triethylamine of O 3.93g (18.0mmol) and catalytic amount at room temperature stirred 8 hours.Reaction solution dilutes with vinyl acetic monomer, water, the 0.5N HCl aqueous solution * 2, saturated NaHCO 3, the salt water washing, use Na 2SO 4Dry.
The filtering siccative after concentrating, washs the solid that obtains with the hexane suspension, obtain title compound (yield 80%).
1H-NMR(CDCl 3)：δ7.31(m，2H)，6.98(m，2H)，6.42(br s，1H)，1.51(s，9H).
B) 2-[methyl (4-fluorophenyl) amino] the ethyl methane sulfonate
Under nitrogen, 0 ℃, in the stirred suspension of 60%NaH 273mg (6.82mmol)/1.5mL, splash into compound 1.20g (the 5.68mmol)/3mLNMP solution that obtains among the embodiment 130a.Stir after 10 minutes, splash into bromo acetic acid ethyl ester 0.995g (5.96mmol), be warming up to room temperature.Stir after 1 hour, reaction solution dilutes with vinyl acetic monomer, and Na is used in water * 4, salt water washing 2SO 4Dry.
The filtering siccative after concentrating, splashes into LiAlH with compound 0.600g (the 2.02mmol)/8mLTHF solution that obtains 4After among 230mg (6.06mmol)/5mL THF, refluxed 4 hours.Reaction solution adds 0.25mL water, the 0.25mL 15%NaOH aqueous solution, 0.75mL water with the dilution of 10mL ether, filters.After filtrate concentrates, that the oily matter that obtains is refining with silica gel chromatography (vinyl acetic monomer/hexane).
The compound 0.401g (2.37mmol) that obtains is dissolved among the methylene dichloride 2mL, adds triethylamine 0.46mL (3.32mmol), be cooled to 0 ℃.To wherein splashing into methane sulfonyl chloride 0.220mL (2.84mmol), stir after 1.5 hours, reaction solution dilutes with ether, and Na is used in water * 3, salt water washing 2SO 4Dry.The filtering siccative after concentrating, obtains title compound.
1H-NMR(CDCl 3)：δ6.95(m，2H)，6.68(m，2H)，4.36(t，J＝5.8Hz，2H)，3.64(t，J＝5.8Hz，2H)，2.69(s，3H)，2.94(s，3H).
C) 2-[[1-[2-[methyl (4-fluorophenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 130b, carry out the operation same with embodiment 26b, the compound of acquisition obtains title compound (yield 60%) without carry out the operation same with embodiment 1f refiningly.223～231 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ10.59(br s，1H)，7.69(d，J＝7.5Hz，1H)，7.61(m，2H)，7.50(m，1H)，7.03(t，J＝9Hz，2H)，6.83(m，2H)，4.51(s，2H)，3.73(m，2H)，2.87-3.54(m，11H)，1.99(m，1H)，1.80(m，2H)，1.59(m，2H).
Embodiment 131:2-[[1-[2-[benzyl (4-fluorophenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 301 of table 1)
A) benzyl (4-fluorophenyl) amine
Methylene dichloride (7mL) solution of 4-fluoroaniline 1.50g (13.5mmol) and triethylamine 2.26mL (16.2mmol) is cooled to 0 ℃, splashes into bromotoluene 1.61mL (13.5mmol).After at room temperature stirring 1 hour, reaction solution dilutes with vinyl acetic monomer, and Na is used in water * 3, saturated common salt water washing 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (vinyl acetic monomer/hexane), obtain title compound (yield 46%).
1H-NMR(CDCl 3)：δ7.26-7.36(m，5H)，6.88(m，2H)，6.56(m，2H)，4.29(s，2H).
B) 2-[benzyl (4-fluorophenyl) amino] the ethyl methane sulfonate
Use the compound that obtains among the embodiment 131a, carry out the operation same, obtain title compound (93%) with embodiment 130b.
1H-NMR(CDCl 3)：δ7.19-7.34(m，5H)，6.91(m，2H)，6.69(m，2H)，4.55(s，2H)，4.34(m，2H)，3.74(m，2H)，2.91(s，3H).
C) 2-[[1-[2-[benzyl (4-fluorophenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 131b, carry out the operation same, obtain title compound (yield 79%) with embodiment 26b.
1H-NMR(CDCl 3)：δ7.86(d，J＝7.2Hz，1H)，7.41-7.58(m，3H)，7.19-7.32(m，5H)，6.87(m，2H)，6.60(m，2H)，4.50(s，2H)，4.39(s，2H)，3.48-3.53(m，4H)，2.90(m，2H)，2.55(m，2H)，2.00(dt，J＝11.7，2.1Hz，2H)，1.78(m，1H)，1.67(m，2H)，1.38(m，2H).
D) 2-[[1-[2-[benzyl (4-fluorophenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 131c, carry out the operation same, obtain title compound (yield 33%) with embodiment 40f.174～185 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.67(d，J＝7.5Hz，1H)，7.59(m，2H)，7.48(m，1H)，7.25(m，2H)，7.20-7.21(m，3H)，6.94(t，J＝8.8Hz，2H)，6.64(m，2H)，5.59(s，2H)，4.53(s，2H)，4.47(s，2H)，3.55(t，J＝7，0Hz，2H)，3.40(d，J＝7.3Hz，2H)，2.98(d，J＝11.4Hz，2H)2.62(t，J＝7.0Hz，2H)，2.14(t，J＝11.2Hz，2H)，1.77(m，1H)，1.59(br d，J＝12Hz，2H)，1.27(m，2H).
Embodiment 132:2-[[1-[2-[(4-fluorophenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 275 of table 1)
A) amino 2-[[1-[2-[(4-fluorophenyl)] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 131c, carry out the operation same, obtain title compound (yield 96%) with embodiment 104a.
1H-NMR(CDCl 3)：δ7.85(d，J＝7.1Hz，1H)，7.42-7.53(m，3H)，6.88(m，2H)，6.55(m，2H)，4.40(s，2H)，3.52(d，J＝7.2Hz，2H)，3.09(t，J＝6.0Hz，2H)，2.89(br d，J＝11.5Hz，2H)，2.59(t，J＝6.0Hz，2H)，1.98(dt，J＝11.5，2.2Hz，2H)，1.79(m，1H)，1.68(br d，J＝12Hz，2H)，1.39(m，2H).
B) amino 2-[[1-[2-[(4-fluorophenyl)] ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 132a, carry out the operation same, obtain title compound with embodiment 1f.221～230 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.69(d，J＝7.4Hz，1H)，7.61(m，2H)，7.50(m，1H)，6.99(m，2H)，6.72(m，2H)，4.51(s，2H)，2.80-3.97(m，10H)，1.99(m，1H)，1.80(m，2H)，1.62(m，2H).
Embodiment 133:2-[[1-[2-[(4-p-methoxy-phenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 307 of table 1)
A) 2-[[1-(2-hydroxyethyl) piperidin-4-yl] methyl] isoindoline-1-ketone is dissolved in compound 1.50g (5.62mmol) and the ethylene bromohyrin 0.703g (5.62mmol) that obtains among the embodiment 1d among the acetonitrile 10mL, add NaI 0.842g (5.62mmol) and salt of wormwood 2.34g (16.9mmol), be heated to 80 ℃.After 3 hours, distillation adds saturated NaHCO after removing and desolvating 3The aqueous solution is used dichloromethane extraction 4 times, uses Na 2SO 4Dry.The filtering siccative after concentrating, washs the solid that obtains with the ether suspension, obtain title compound (yield 76%).
1H-NMR(CDCl 3)：δ7.85(d，J＝7.5Hz，1H)，7.44-7.56(m，3H)，4.41(s，2H)，3.59(t，J＝5.4Hz，2H)，3.51(d，J＝7.5Hz，2H)，2.91(br d，J＝12Hz，2H)，2.51(t，J＝5.4Hz，2H)，2.06(dt，J＝11.7，2.4Hz，2H)，1.83(m，1H)，1.70(br d，J＝12Hz，2H)，1.39(m，2H).
B) 2-[[1-(2-mesyloxy ethyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
The compound 1.00g (4.20mmol) that obtains among the embodiment 133a and methylene dichloride (5mL) solution of triethylamine 0.88mL (6.31mmol) are cooled to 0 ℃, splash into methylsulfonyl chloride 0.488mL (6.31mmol).Be warming up to room temperature, stir after 1 hour, reaction solution dilutes with vinyl acetic monomer, uses saturated NaHCO 3Na is used in the aqueous solution, water * 2, saturated common salt water washing 2SO 4Dry.Behind the filtering siccative,, filter the crystallization of separating out, obtain title compound (49%) with 1.30mL 4N HCl-AcOEt solution-treated.
1H-NMR(DMSO-d 6)：δ10.61(br s，1H)，7.69(d，J＝7.5Hz，1H)，7.61(m，2H)，7.49(m，1H)，4.51(s，2H)，4.04(t，J＝6.9Hz，2H)，2.88-3.62(m，11H)，1.99(m，1H)，1.80(m，2H)，1.59(m，2H).
C) amino 2-[[1-[2-[(4-p-methoxy-phenyl)] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Add sodium iodide 77mg (0.51mmol) and salt of wormwood 178mg (1.29mmol) in acetonitrile (2mL) solution of compound 200mg (0.514mmol) that in embodiment 133b, obtains and P-nethoxyaniline 63mg (0.51mmol), be heated to 70 ℃.After 2 hours, distillation removes and desolvates, and adds the saturated aqueous common salt and the 1N NaOH aqueous solution then, uses dichloromethane extraction 3 times, uses Na 2SO 4Dry.The filtering siccative, refining after concentrating with silica gel chromatography (methylene chloride), obtain title compound (yield 47%).
1H-NMR(CDCl 3)：δ7.85(d，J＝7.2Hz，1H)，7.42-7.53(m，3H)，6.79(d，J＝9.0Hz，2H)，6.60(d，J＝9.0Hz，2H)，4.40(s，2H)，3.75(s，3H)，3.51(d，J＝7.2Hz，2H)，3.10(t，J＝6.0Hz，2H)，2.90(br d，J＝11.7Hz，2H)，2.59(t，J＝6.0Hz，2H)，1.98(dt，J＝11.7，2.1Hz，2H)，1.81(m，1H)，1.68(br d，J＝12Hz，2H)，1.40(m，2H).
D) amino 2-[[1-[2-[(4-p-methoxy-phenyl)] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 133c, carry out the operation same, obtain title compound (yield 84%) with embodiment 40f.202 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.67(d，J＝7.5Hz，1H)，7.59(m，2H)，7.49(m，1H)，6.71(d，J＝9Hz，2H)，6.58(s，2H)，6.54(d，J＝9Hz，2H)，4.48(s，2H)，3.63(s，3H)，3.42(d，J＝7.2Hz，2H)，3.12(t，J＝6.6Hz，2H)，3.03(d，J＝12Hz，2H)，2.66(t，J＝6.6Hz，2H)，2.21(t，J＝12Hz，2H)，1.81(m，1H)，1.63(br d，J＝12Hz，2H)，1.31(m，2H).
Embodiment 134:2-[[1-[2-[(3-p-methoxy-phenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 313 of table 1)
A) amino 2-[[1-[2-[(3-p-methoxy-phenyl)] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use m-anisidine, carry out the operation same, obtain title compound (yield 31%) with embodiment 133c.
1H-NMR(CDCl 3)：δ7.85(d，J＝7.5Hz，1H)，7.42-7.53(m，3H)，7.08(t，J＝8.1Hz，1H)，6.26(m，2H)，6.18(m，1H)，4.40(s，2H)，3.78(s，3H)，3.52(d，J＝7.2Hz，2H)，3.14(t，J＝6.0Hz，2H)，2.91(br d，J＝11.7Hz，2H)，2.60(t，J＝6.0Hz，2H)，1.99(br t，J＝12Hz，2H)，1.82(m，1H)，1.68(m，2H)，1.40(m，2H).
B) amino 2-[[1-[2-[(3-p-methoxy-phenyl)] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 134a, carry out the operation same, obtain title compound (yield 88%) with embodiment 40f.Fusing point 178-182 ℃
1H-NMR(DMSO-d 6)：δ7.67(d，J＝7.5Hz，1H)，7.60(m，2H)，7.50(m，1H)，6.96(t，J＝8.4Hz，1H)，6.58(s，2H)，6.11-6.19(m，3H)，4.48(s，2H)，3.66(s，3H)，3.42(d，J＝7.2Hz，2H)，3.16(t，J＝6.6Hz，2H)，3.02(br d，J＝11.7Hz，2H)，2.65(t，J＝6.6Hz，2H)，2.20(br t，J＝12Hz，2H)，1.82(m，1H)，1.63(br d，J＝12Hz，2H)，1.31(m，2H).
Embodiment 135:2-[[1-[2-[(2-p-methoxy-phenyl) amino] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 319 of table 1)
A) amino 2-[[1-[2-[(2-p-methoxy-phenyl)] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use ORTHO ANISIDINE, carry out the operation same, obtain title compound (yield 36%) with embodiment 133c.
1H-NMR(CDCl 3)：δ7.85(d，J＝7.5Hz，1H)，7.45-7.53(m，3H)，6.86(m，1H)，6.77(m，1H)，6.58-6.67(m，2H)，4.40(s，2H)，3.86(s，3H)，3.52(d，J＝7.5Hz，2H)，3.19(t，J＝6.0Hz，2H)，2.93(br d，J＝11.4Hz，2H)，2.64(t，J＝6.0Hz，2H)，1.99(m，2H)，1.80(m，1H)，1.68(m，2H)，1.41(m，2H).
B) amino 2-[[1-[2-[(2-p-methoxy-phenyl)] ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 135a, carry out the operation same, obtain title compound (yield 89%) with embodiment 40f.183～191 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.67(d，J＝7.5Hz，1H)，7.59(m，2H)，7.48(m，1H)，6.75-6.81(m，2H)，6.58(s，2H)，6.56(m，2H)，4.49(s，2H)，3.77(s，3H)，3.43(d，J＝7.3Hz，2H)，3.18(t，J＝6.3Hz，2H)，3.00(br d，J＝11Hz，2H)，2.69(t，J＝6.3Hz，2H)，2.17(m，2H)，1.81(m，1H)，1.63(m，2H)，1.28(m，2H).
Embodiment 136:2-[[1-[2-(4-fluorophenyl) allyl group] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 358 of table 1)
Make first base three phenyl phosphonium bromides (801mg 2.24mmol) is suspended in the tetrahydrofuran (THF) (4ml), at room temperature add potassium tert.-butoxide (257mg, 2.29mmol).(819mg 2.24mmol) is dissolved in solution in the tetrahydrofuran (THF) (4ml) to the compound that obtains in wherein adding embodiment 1e, stirs 1 hour under uniform temp.Reaction solution dilutes with vinyl acetic monomer, after saturated sodium bicarbonate water, water, saturated common salt water washing, uses dried over sodium sulfate.Filter insolubles, decompression is concentrated filtrate down, obtains crude product 2-[[1-[2-(4-fluorophenyl) allyl group] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound (yield 34%) of colorless solid with embodiment 1f.173～181 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.6-10.0(1H，brs，HCl)，7.59-7.70(5H，m)，7.45-7.51(1H，m)，7.22-7.30(2H，m)，5.79(1H，s)，5.72(1H，s)，4.48(2H，s)，4.37-4.40(0.4H，m)，4.20-4.23(1.6H，m)，3.1-3.6(4H，m)，2.7-2.9(2H，m)，1.4-2.2(5H，m)
Embodiment 137:2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-3,4-dihydro-isoquinoline-1 (2H)-keto hydrochloride (compound 761 of table 1)
A) 4-(4-Methyl benzenesulfonyl oxygen ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
With 4-hydroxymethyl piperidine-1-carboxylic acid tert-butyl ester (opening flat 11-217377 with reference to the spy synthesizes) (12.12g, 56.30mmol) be dissolved in the methylene dichloride (26ml), at room temperature add Tosyl chloride (10.73g, 56.30mmol), triethylamine (8.63mmol, 61.9mmol), under uniform temp, stirred 5 hours.Reaction solution dilutes with methylene dichloride (100ml), and water, saturated common salt water washing after dried over sodium sulfate, are filtered insolubles, and filtrate is removed in underpressure distillation.With hexane (100ml) recrystallization, obtain the title compound 14.13g (yield 85%) of colorless solid.
1H-NMR(CDCl 3)：7.78(2H，d，J＝8.1Hz)，7.35(2H，d，J＝8.4Hz)，4.09(2H，brs)，3.85(2H，d，J＝6.9Hz)，2.65(2H，brdd，J＝12.5，12.5Hz)，2.46(3H，s)，1.87-1.79(1H，m)，1.65-1.62(2H，m)，1.44(9H，s)，1.17-1.03(2H，m).
B) 4-[3,4-dihydro-isoquinoline-2 (1H)-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
With the compound that obtains among the embodiment 137a (1.0g, 2.71mmol), (375mg, 2.71mmol), 3, (399mg 2.71mmol) was dissolved in the dimethyl formamide (9ml) the 4-dihydro-isoquinoline salt of wormwood, 80 ℃ of following heated and stirred 13 hours.With reaction solution put cold after, with vinyl acetic monomer dilution, wash with water, after dried over sodium sulfate, filter insolubles, filtrate is removed in underpressure distillation.The crude product that obtains is refining with silica gel column chromatography (methyl alcohol-methylene dichloride), the title compound 948mg (quantitative yield) of acquisition colorless oil.
1H-NMR(CDCl 3)：7.20-7.07(3H，m)，7.02-7.00(1H，m)，4.11(2H，brs)，3.60(2H，s)，2.91-2.87(2H，m)，2.76-2.68(4H，m)，2.35(2H，d，J＝6.6Hz)，1.80-1.68(3H，m)，1.46(9H，s)，1.18-1.09(2H，m).
C) 4-[[1-oxo-3,4-dihydro-isoquinoline-2 (1H)-yl] methyl] the piperidine carboxylic acid tert-butyl ester
With the compound that obtains among the embodiment 137b (488mg 1.48mmol) is dissolved in the methylene dichloride (15ml), add potassium permanganate (702mg, 4.44mmol), 3-ethyl benzyl ammonium chloride (337mg, 1.48mmol), reflux 5.5 hours.Put cold after, add saturated SODIUM HYDROSULPHITE sodium water solution (15ml), stir after 20 minutes, with the reaction solution dichloromethane extraction.After washing with water, use dried over sodium sulfate, filter insolubles.After filtrate is removed in underpressure distillation, refining with silica gel column chromatography (methyl alcohol-methylene dichloride), the title compound 281mg (yield 55%) of acquisition colorless oil.
1H-NMR(CDCl 3)：8.07(1H，dd，J＝7.5，1.2Hz)，7.45-7.32(2H，m)，7.19-7.17(1H，m)，4.10(2H，brs)，3.57(2H，dd，J＝6.6，6.6Hz)，3.00(2H，dd，J＝6.6，6.6Hz)，3.02(2H，brs)，2.69(2H，brdd，J＝12.1，12.1Hz)，1.96-1.90(1H，m)，1.72-1.62(2H，m)，1.46(9H，s)，1.31-1.18(2H，m)
D) 2-(piperidin-4-yl methyl)-3,4-dihydro-isoquinoline-1 (2H)-keto hydrochloride
Use the crude product (281mg) that obtains among the embodiment 137c, carry out the operation same, obtain the title compound 232mg (quantitative yield) of colorless solid with embodiment 1d.
E) 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-3,4-dihydro-isoquinoline-1 (2H)-ketone
(230mg 0.82mmol), carries out the operation same with embodiment 1e, obtains the title compound 110mg (yield 35%) of brown oil to use the compound that obtains among the embodiment 137d.
1H-NMR(CDCl 3)：8.10-8.05(3H，m)，7.43-7.33(2H，m)，7.19-7.09(3H，m)，3.73(2H，s)，3.57(2H，dd，J＝6.8，6.8Hz)，3.45(2H，d，J7.2Hz)，3.01-2.95(4H，m)，2.15(2H，ddd，J＝1.1，11.5，11.5Hz)，1.83-1.44(5H，m).
F) 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-3,4-dihydro-isoquinoline-1 (2H)-keto hydrochloride
(110mg 0.29mmol), carries out the operation same with embodiment 1f, obtains filbert solid title compound 80mg (yield 66%) to use the compound that obtains among the embodiment 137e.151～156 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.02(1H，brs)，8.19-8.06(2H，m)，7.87(1H，d，J＝7.8Hz)，7.51-7.45(3H，m)，7.38-7.29(2H，m)，5.11-5.04(2H，m)，3.60-3.53(4H，m)，3.44-3.37(2H，m)，3.07-2.98(4H，m)，1.99-1.07(5H，m).
Embodiment 138:2-[[1-[(E)-and 2-(4-fluorophenyl)-2-methoxyimino ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the compound 741E body of table 1)
A) 2-[[1-[(E)-and 2-(4-fluorophenyl)-2-methoxyimino ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone, 2-[[1-[(Z)-2-(4-fluorophenyl)-2-methoxyimino ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound and the methoxy amine hydrochlorate that obtain among the embodiment 1e, carry out the operation same, obtain title compound with embodiment 18a.
2-[[1-[(E)-and 2-(4-fluorophenyl)-2-methoxyimino ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone (yield 30%)
1H-NMR(CDCl 3)：δ7.84(d，J＝7.5Hz，1H)，7.78(m，2H)，7.41-7.52(m，3H)，7.01(t，J＝9Hz，2H)，4.37(s，2H)，3.94(s，3H)，3.57(s，2H)，3.46(d，J＝7.4Hz，2H)，2.82(br d，J＝11.6Hz，2H)，2.04(t，J＝10Hz，2H)，1.74(m，1H)，1.59(m，2H)，1.30(m，2H).
2-[[1-[(Z)-and 2-(4-fluorophenyl)-2-methoxyimino ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone (yield 6%)
1H-NMR(CDCl 3)：δ7.84(d，J＝7.5Hz，1H)，7.59(m，2H)，7.42-7.53(m，3H)，7.05(t，J＝8.9Hz，2H)，4.38(s，2H)，3.86(s，3H)，3.48(d，J＝7.3Hz，2H)，3.30(s，2H)，2.91(br d，J＝11.6Hz，2H)，2.01(br t，J＝11Hz，2H)，1.76(m，1H)，1.62(m，2H)，1.33(m，2H).
B) 2-[[1-[(E)-and 2-(4-fluorophenyl)-2-methoxyimino ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 138a, carry out the operation same, obtain title compound (yield 66%) with embodiment 40f.176 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.79(m，2H)，7.65(d，J＝7.5Hz，1H)，7.58(m，2H)，7.49(m，1H)，7.21(m，2H)，6.63(s，2H)，4.45(s，2H)，3.88(s，3H)，3.59(s，2H)，3.35(d，J＝7.3Hz，2H)，2.76(br d，J＝11.5Hz，2H)，1.99(brt，J＝10Hz，2H)，1.69(m，1H)，1.51(br d，J＝11.4Hz，2H)，1.08(m，2H).
Embodiment 139:2-[[1-[(Z)-and 2-(4-fluorophenyl)-2-methoxyimino ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the compound 741Z body of table 1)
Use embodiment 138a) the middle compound that obtains, carry out 40f with embodiment) same operation, obtain title compound (yield 91%).164 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ7.65(d，J＝7.5Hz，1H)，7.55-7.62(m，4H)，7.47(m，1H)，7.23(t，J＝8.9Hz，2H)，6.61(s，2H)，4.49(s，2H)，3.75(s，3H)，3.35(d，J＝7.4Hz，2H)，3.30(s，2H)，2.80(br d，J＝11.5Hz，2H)，1.93(brt，J＝11Hz，2H)，1.68(m，1H)，1.52(br d，J＝11.8Hz，2H)，1.07(m，2H).
Embodiment 140:2-[[1-[(E)-and 2-(4-fluorophenyl)-2-methoxycarbonyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone 1/4 fumarate (the compound 746E body of table 1)
A) 2-[[1-[(E)-and 2-(4-fluorophenyl)-2-methoxycarbonyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound and the diazanyl carboxylate methyl ester that obtain among the embodiment 1e, carry out the operation same, obtain title compound with embodiment 18a.(yield 46%)
1H-NMR(CDCl 3)：δ11.95(s，1H)，7.85(d，J＝6.9Hz，1H)，7.68(m，2H)，7.43-7.55(m，3H)，7.03(t，J＝9Hz，2H)，4.41(s，2H)，3.85(s，3H)，3.64(s，2H)，3.54(d，J＝7.2Hz，2H)，2.95(br d，J＝11Hz，2H)，2.08(br t，J＝11Hz，2H)，1.87(m，1H)，1.76(br d，J＝12Hz，2H)，1.44(m，2H).
2-[[1-[(Z)-and 2-(4-fluorophenyl)-2-methoxycarbonyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone (yield 15%)
1H-NMR(CDCl 3)：δ7.84(d，J＝7.2Hz，1H)，7.45-7.53(m，3H)，7.28(m，2H)，7.18(t，J＝9Hz，2H)，4.38(s，2H)，3.78(br s，3H)，3.47(d，J＝7.5Hz，2H)，3.36(s，2H)，2.85(br d，J＝11Hz，2H)，2.06(br t，J＝10Hz，2H)，1.72(m，1H)，1.61(m，2H)，1.28(m，2H).
B) 2-[[1-[(E)-and 2-(4-fluorophenyl)-2-methoxycarbonyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone 1/4 fumarate
Use the compound that obtains among the embodiment 140a, carry out the operation same, obtain title compound (yield 76%) with embodiment 40f.154 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ12.08(br s，1H)，7.75(m，2H)，7.67(d，J＝7.5Hz，1H)，7.59(m，2H)，7.50(m，1H)，7.22(t，J＝9Hz，2H)，6.63(s，0.5H)，4.48(s，2H)，3.73(s，2H)，3.71(s，3H)，3.42(d，J＝7.2Hz，2H)，2.82(br d，J＝12Hz，2H)，2.08(br t，J＝11Hz，2H)，1.77(m，1H)，1.64(br d，J＝12Hz，2H)，1.18(m，2H).
Embodiment 141:2-[[1-[(Z)-and 2-(4-fluorophenyl)-2-methoxycarbonyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the compound 746Z body of table 1)
Use the compound that obtains among the embodiment 140a, carry out the operation same, obtain title compound (yield 73%) with embodiment 40f.153 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.39(s，1H)，7.65(d，J＝7.5Hz，1H)，7.58(m，2H)，7.48(m，1H)，7.38(m，2H)，7.27(t，J＝9Hz，2H)，6.62(s，2H)，4.45(s，2H)，3.60(s，3H)，3.35(d，J＝7.5Hz，2H)，3.32(s，2H)，2.80(br d，J＝11Hz，2H)，1.98(m，2H)，1.70(m，1H)，1.52(m，2H)，1.07(m，2H).
Embodiment 142:2-[[1-[(E)-and 2-(4-fluorophenyl)-2-ethanoyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the compound 751E body of table 1)
A) 2-[[1-[(E)-and 2-(4-fluorophenyl)-2-ethanoyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound and the acethydrazide [ア セ チ Star Network ヒ De ラ ジ De] that obtain among the embodiment 1e, carry out the operation same, obtain title compound with embodiment 18a.(yield 64%)
1H-NMR(CDCl 3)：δ11.98(s，1H)，7.84(d，J＝7.2Hz，1H)，7.67(m，2H)，7.24-7.54(m，3H)，7.06(t，J＝8.7Hz，2H)，4.41(s，2H)，3.63(s，2H)，3.51(d，J＝7.5Hz，2H)，2.91(br d，J＝11.4Hz，2H)，2.32(s，3H)，2.09(br t，J＝10Hz，2H)，1.83(m，1H)，1.76(br d，J＝12Hz，2H)，1.47(m，2H).
B) 2-[[1-[(E)-and 2-(4-fluorophenyl)-2-ethanoyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 142a, carry out the operation same, obtain title compound (yield 75%) with embodiment 40f.168～170 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ12.06(s，1H)，7.80(m，2H)，7.67(d，J＝7.5Hz，1H)，7.59(m，2H)，7.48(m，1H)，7.23(t，J＝9Hz，2H)，4.48(s，2H)，3.75(s，2H)，3.42(d，J＝7.2Hz，2H)，2.83(br d，J＝11Hz，2H)，2.20(s，3H)，2.08(br t，J＝11Hz，2H)，1.76(m，1H)，1.64(br d，J＝12Hz，2H)，1.19(m，2H).
Embodiment 143:2-[[1-[(Z)-and 2-(4-fluorophenyl)-2-ethanoyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (the compound 751Z body of table 1)
A) N '-[2-chloro-1-(4-fluorophenyl) ethylidene] acethydrazide [ア セ ト ヒ De ラ ジ De]
With 2-chloro-4 '-fluoro acetophenone 1.00g (5.79mmol) and acethydrazide 0.472g (6.37mmol) be dissolved among the ethanol 10mL, at room temperature stirred 8 hours.After reaction solution concentrated, residual solid was with the hexane washing that suspends, and it is refining with silica gel column chromatography (methylene dichloride/vinyl acetic monomer), obtains title compound (yield 94%).
1H-NMR(CDCl 3)：δ9.19(br s，1H)，7.75(m，2H)，7.12(m，2H)，4.44(s，2H)，2.41(s，3H).
B) 2-[[1-[(Z)-and 2-(4-fluorophenyl)-2-ethanoyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 143a, carry out the operation same with embodiment 1f, refining with silica gel chromatography (methylene chloride), obtain title compound (yield 53%).
1H-NMR(CDCl 3)：δ8.29(s，1H)，7.85(d，J＝7.2Hz，1H)，7.42-7.54(m，3H)，7.24(m，2H)，7.16(t，J＝8.7Hz，2H)，4.39(s，2H)，3.49(d，J＝7.2Hz，2H)，3.30(s，2H)，2.90(br d，J＝11.7Hz，2H)，2.30(s，3H)，2.06(m，2H)，1.78(m，1H)，1.65(m，2H)，1.34(m，2H).
C) 2-[[1-[(Z)-and 2-(4-fluorophenyl)-2-ethanoyl hydrazono-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 143b, carry out the operation same, obtain title compound (yield 63%) with embodiment 40f.157 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ9.34-9.92(m，1H)，7.66(d，J＝7.2Hz，1H)，7.58(m，2H)，7.40-7.57(m，3H)，7.31(t，J＝9.0Hz，2H)，6.62(s，2H)，4.45(s，2H)，3.35-3.40(m，4H)，2.83(m，2H)，1.82-2.15(m，5H)，1.71(m，1H)，1.53(m，2H)，1.08(m，2H).
Embodiment 144:(E, Z) 2-[[1-[2-(4-fluorophenyl)-2-(benzyloxy) imino-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 756 of table 1)
With the compound that obtains among the embodiment 1e (581mg, 1.59mmol), (568mg 3.56mmol) is dissolved in pyridine (12ml)-ethanol (12ml) mixed solvent the benzyloxy amine hydrochlorate, at room temperature stirs 3 days.Reaction solution dilutes with vinyl acetic monomer, after saturated sodium bicarbonate water, saturated common salt water washing, uses dried over sodium sulfate.Filter insolubles, concentrating under reduced pressure filtrate, the acquisition crude product (E, Z) 2-[[1-[2-(4-fluorophenyl)-2-(benzyloxy) imino-ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone.Carry out the operation same with it, obtain the title compound 255mg (yield 27%) of colorless solid with embodiment 36c.151～155 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.18-7.78(13H，m)，6.63(2H，s，fumaric acid)，5.17(0.8H，s)，5.07(1.2H，s)，4.45(2H，s)，3.63(0.8H，s)，3.2-3.4(3.2H，m)，2.70-2.80(2H，m)，1.86-2.03(2H，m)，1.6-1.8(1H，m)，1.4-1.5(2H，m)，0.9-1.1(2H，m)
Embodiment 145:2-[[1[(E)-and 3-phenyl third-2-thiazolinyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (the compound 364E body of table 1)
A) 2-[[1[(E)-and 3-phenyl third-2-thiazolinyl] piperidin-4-yl] methyl] isoindoline-1-ketone
With the compound that obtains among the embodiment 1e (500mg, 1.87mmol) and 3-bromo-1-phenyl-1-propylene (369mg 1.87mmol) is dissolved in the dimethyl formamide (6ml), and (516mg 3.74mmol), at room temperature stirred 20 hours to add salt of wormwood.In reaction solution, add entry (20ml), filter and collect the solid of separating out, obtain the title compound 402mg (yield 62%) of colorless solid.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.0Hz)，7.83-7.22(8H，m)，6.50(1H，d，J＝16.0Hz)，6.28(1H，dt，J＝15.8，6.7Hz)，4.41(2H，s)，3.51(2H，d，J＝7.1Hz)，3.14(2H，d，J＝6.7Hz)，2.98(2H，brd，J＝11.0Hz)，1.97(2H，dd，J＝11.4Hz)，1.86-1.69(3H，m)，1.42(2H，ddd，J＝24.5，12.5，2.9Hz).
B) 2-[[1[(E)-and 3-phenyl third-2-thiazolinyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 145a, carry out the reaction same, obtain the title compound 197mg (yield 45%) of colorless solid with embodiment 1f.212～215 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.8(1H，m)，7.68(1H，d，J＝4.8Hz)，7.61(2H，d，J＝3.9Hz)，7.53-7.46(3H，m)，7.41-7.30(3H，m)，6.81(1H，d，J＝15.9Hz)，6.43(1H，dt，J＝15.9，7.6Hz)，4.51(2H，s)，3.84(2H，s)，3.44(2H，d，J＝6.9Hz)，3.35(2H，s)，2.90-2.87(2H，m)，1.99(1H，brs)，1.81(2H，brd，J＝13.5Hz)，1.57(2H，brdd，J＝15.2，11.6Hz).
Embodiment 146:2-[[1[(z)-and 3-phenyl third-2-thiazolinyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (the compound 364Z body of table 1)
A) (Z)-3-phenyl third-2-alkene-1-alcohol
(500mg 3.78mmol) is dissolved in the ethanol (3ml), and Lindlar catalyzer (25mg) is suspended, and stirs 6 hours under hydrogen stream with 3-phenyl third-2-alkynes-1-alcohol.Filtering reacting liquid, refining behind the concentrated filtrate with silica gel column chromatography (methylene dichloride), the title compound of acquisition yellow oil (500mg, quantitatively).
1H-NMR(CDCl 3)：7.41-7.19(5H，m)，6.58(1H，d，J＝11.7Hz)，5.88(1H，dt，J＝11.7，6.2Hz)，4.44(2H，dd，J＝6.3，1.5Hz).
B) (Z)-3-chloro-1-phenyl third-1-alkene
With the compound that obtains among the embodiment 146a (300mg 2.24mmol) is dissolved in the methylene dichloride (7ml), ice-cold add down the chlorination tolysulfonyl (427mg, 2.24mmol) and triethylamine (0.31ml, 2.24mmol) after, return room temperature, stirred 16 hours.Add entry (10ml) in reaction solution, behind dichloromethane extraction, dried over sodium sulfate is used in water, saturated common salt water washing.Filter insolubles, refining after filtrate is removed in underpressure distillation with silica gel column chromatography (hexane), the title compound 113mg (yield 33%) of acquisition colorless oil.
1H-NMR(CDCl 3)：7.41-7.26(5H，m)，6.66(1H，d，J＝11.4Hz)，5.90(1H，dt，J＝11.4，8.2Hz)，4.27(2H，d，J＝6.9Hz).
C) 2-[[1[(Z)-and 3-phenyl third-2-thiazolinyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 146b (110mg, 0.721mmol) and the compound that obtains among the embodiment 1d (183mg 0.685mmol), carries out the reaction same with embodiment 145a, obtains the title compound 236mg (quantitative yield) of colorless solid.
1H-NMR(CDCl 3)：7.84(1H，d，J＝7.5Hz)，7.54-7.21(8H，m)，6.55(1H，d，J＝11.9Hz)，5.79(1H，dt，J＝11.2，6.1Hz)，4.40(2H，s)，3.50(2H，d，J＝7.0Hz)，3.26(2H，dd，J＝6.1，1.2Hz)，2.96(2H，brd，J＝8.3Hz)1.98-1.87(2H，m)，1.79-1.67(3H，m)，1.48-1.40(2H，m).
D) 2-[[1[(Z)-and 3-phenyl third-2-thiazolinyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use compound (230mg 0.664mmol), carries out the reaction same with embodiment 1f, obtains the title compound 148mg of the colorless solid) yield 58% that obtains among the embodiment 146c).206～215 ℃ of fusing points (decomposition)
1H-NMR(DMSO-d 6)：10.96(1H，brs)，7.68(1H，d，J＝7.2Hz)，7.60(2H，d，J＝3.9Hz)，6.83(1H，d，J＝12.0Hz)，6.00(1H，dt，J＝11.7，6.2Hz)，4.49(2H，s)，4.11-3.99(2H，m)，3.62-3.41(2H，m)，2.85(2H，brdd，J＝21.8，10.1Hz)，1.99-1.91(1H，m)，1.78(2H，brd，J＝12.3Hz)，1.62(2H，brd，J＝23.7，12.3Hz).
Embodiment 147:2-[[1-(3-phenyl Propargyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 370 of table 1)
A) 3-fluoro-1-phenyl third-1-alkynes
(300mg 2.27mmol), carries out the reaction same with embodiment 146b, obtains the title compound 99mg (yield 29%) of colorless oil to use 3-phenyl third-2-alkynes-1-alcohol.
1H-NMR(CDCl 3)：7.47-7.44(2H，m)，7.45-7.32(3H，m)，4.38(2H，s).
B) 2-[[1-(3-phenyl Propargyl) piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 147a (99mg, 0.657mmol) and the compound that obtains among the embodiment 1d (158mg 0.591mmol), carries out the reaction same with embodiment 145a, obtains the title compound 163mg (yield 80%) of colorless solid.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5Hz)，7.56-7.41(5H，m)，7.31-7.26(3H，m)，4.42(2H，s)，3.53-3.51(4H，m)，2.98(2H，brd，J＝12.6Hz)，2.27(2H，ddd，J＝2.2，11.6，11.6Hz)，1.85-1.73(3H，m)，1.53-1.43(2H，m).
C) 2-[[1-(3-phenyl Propargyl) piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
(160mg 0.465mmol), carries out the reaction same with embodiment 1f, obtains the title compound 138mg (yield 78%) of colorless solid to use the compound that obtains among the embodiment 147b.205～211 ℃ of fusing points
1H-NMR(DMSO-d 6)：11.16(1H，brs)，7.70-7.43(9H，m)，4.52(2H，s)，4.31(2H，s)，3.57-3.36(4H，m)，3.02(2H，brs)，2.03-1.59(5H，m).
Embodiment 148:2-[[1-[2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 576 of table 1)
A) 2-(hydroxyethyl) isoindoline-1-ketone methanesulfonates
Use the compound and the 2-monoethanolamine that obtain among the embodiment 1b, carry out the operation same, obtain crude product 2-(hydroxyethyl) isoindoline-1-ketone with embodiment 1c.Carry out the operation same with it, obtain the title compound (yield 30%) of colorless solid with embodiment 26a.
B) 2-[[1-[2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 148b, carry out the operation same, obtain the title compound (yield 72%) of faint yellow oily thing with embodiment 26b.
1H-NMR(CDCl 3)：7.84(2H，d，J＝7.2)，7.41-7.56(6H，m)，4.51(2H，s)，4.39(2H，s)，3.72(2H，t，J＝6.3)，3.50(2H，d，J＝7.2)，2.92-3.00(2H，m)，2.62(2H，t，J＝6.3)，1.95-2.06(2H，m)，1.5-1.9(3H，m)，1.2-1.4(2H，m)
C) 2-[[1-[2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 148b, carry out the operation same, obtain the title compound (yield 51%) of colorless solid with embodiment 1f.212～218 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.6-10.0(1H，broad，HCl)，7.56-7.73(6H，m)，7.45-7.54(2H，m)，4.55(2H，s)，4.50(2H，s)，3.93(2H，t，J＝6.0)，3.58-3.68(2H，m)，3.3-3.5(4H，m)，2.84-2.98(2H，m)，1.9-2.1(1H，m)，1.7-1.9(2H，m)，1.3-1.7(2H，m)
Embodiment 149:2-[[1-[3-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) propyl group] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 581 of table 1)
A) 3-(hydroxypropyl) isoindoline-1-ketone methanesulfonates
Use the compound and the 3-aminopropanol that obtain among the embodiment 1b, carry out the operation same, obtain crude product 3-(hydroxypropyl) isoindoline-1-ketone with embodiment 1c.Carry out the operation same with it, obtain the title compound (yield 38%) of colorless solid with embodiment 26a.
B) 2-[[1-[3-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 149b, carry out the operation same, obtain the title compound (yield 54%) of yellow solid with embodiment 26b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝6.0)，7.83(1H，d，J＝6.3)，7.41-7.56(6H，m)，4.39(4H，s)，3.65(2H，t，J＝7.1)，3.48(2H，d，J＝7.2)，2.87-3.95(2H，m)，2.39(2H，t，J＝7.4)，1.5-1.9(7H，m)，1.2-1.4(2H，m)
C) 2-[[1-[2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 149b, carry out the operation same, obtain the title compound (yield 58%) of colorless solid with embodiment 1f.236～246 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.8-10.0(1H，broad，HCl)，7.68(2H，d，J＝7.3)，7.56-7.65(4H，m)，7.45-7.53(2H，m)，4.52(2H，s)，4.50(2H，s)，3.60(2H，t，J＝6.6)，3.0-3.5(4H，m)，2.9-3.0(2H，m)，2.6-2.8(2H，m)，1.8-2.2(3H，m)，1.6-1.8(2H，m)，1.3-1.6(2H，m)
Embodiment 150:2-[[1-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 586 of table 1)
A) 4-(hydroxyl butyl) isoindoline-1-ketone methanesulfonates
Use the compound and the 4-amino butanol that obtain among the embodiment 1b, carry out the operation same, obtain crude product 4-(hydroxyl butyl) isoindoline-1-ketone with embodiment 1c.Carry out the operation same with it, obtain the title compound (yield 43%) of colorless oil with embodiment 26a.
B) 2-[[1-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) butyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 150b, carry out the operation same, obtain the title compound (yield 87%) of yellow solid with embodiment 26b.
1H-NMR(CDCl 3)：7.84(1H，d，J＝6.6)，7.83(1H，d，J＝6.9)，7.42-7.56(6H，m)，4.39(2H，s)，4.37(2H，s)，3.63(2H，t，J＝7.1)，3.49(2H，d，J＝7.2)，2.84-2.92(2H，m)，2.34(2H，t，J＝7.5)，1.4-1.9(9H，m)，1.2-1.4(2H，m)
C) 2-[[1-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) butyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 150b, carry out the operation same, obtain the title compound (yield 87%) of colorless solid with embodiment 1f.207～216 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.1-10.4(1H，broad，HCl)，7.68(2H，d，J＝7.5)，7.56-7.65(4H，m)，7.46-7.53(2H，m)，4.50(4H，s)，3.50-3.62(2H，m)，3.0-3.5(4H，m)，2.9-3.0(2H，m)，2.6-2.8(2H，m)，1.4-2.2(9H，m)
Embodiment 151:2-[[1-[3-[2-oxo-3,4-dihydroquinoline-1 (2H)-yl] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 601 of table 1)
A) 1-(3-hydroxypropyl)-3,4-dihydroquinoline-2 (1H)-ketone
With 3, (1.20g 8.15mmol) is dissolved in the dimethyl formamide (10ml) 4-dihydro-2 (1H)-quinolinone [キ ノ リ ノ Application], and (376mg 9.40mmol), stirred 30 minutes under uniform temp to add 60% sodium hydride under the room temperature.(1.94g 8.70mmol), heated 1 hour at 70 ℃ to wherein adding 2-(3-bromine propoxy-) tetrahydrochysene-2H-pyrans.Reaction solution is cooled to room temperature, and dilute with water with vinyl acetic monomer-hexane mixed extractant solvent, after the saturated common salt water washing, is used dried over mgso.Filter insolubles, concentrating under reduced pressure filtrate.The oily matter that obtains is dissolved in the methyl alcohol (90ml), adds the tosic acid of catalytic amount, stirred 19 hours under the room temperature.Behind the reaction solvent concentrating under reduced pressure,, after saturated sodium bicarbonate water, saturated common salt water washing, use dried over mgso with the vinyl acetic monomer dilution.Filter insolubles, concentrating under reduced pressure filtrate, the oily matter that obtains is refining with silica gel column chromatography (vinyl acetic monomer-hexane), the title compound 1.47g (yield 88%) of acquisition colorless oil.
1H-NMR(CDCl 3)：7.15-7.29(2H，m)，7.00-7.11(2H，m)，4.12(2H，t，J＝6.2)，3.56(2H，t，J＝5.6)，3.38(1H，brs，OH)，2.89-2.96(2H，m)，2.67-2.74(2H，m)，1.83-1.94(2H，m)
B) 2-[[1-[3-[2-oxo-3,4-dihydroquinoline-1 (2H)-yl] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 151a, carry out the operation same, obtain crude product 1-(3-hydroxypropyl)-3,4-dihydroquinoline-2 (1H)-ketone methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 59%) of yellow oil with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.4)，7.41-7.54(3H，m)，7.20-7.26(1H，m)，7.15(1H，d，J＝7.2)，7.08(1H，d，J＝8.0)，6.99(1H，t，J＝7.6)，4.40(2H，s)，3.96(2H，t，J＝7.5)，3.51(2H，d，J＝7.2)，2.84-2.96(4H，m)，2.59-2.67(2H，m)，2.34-2.43(2H，m)，1.6-2.1(7H，m)，1.3-1.5(2H，m)
C) 2-[[1-[3-[2-oxo-3,4-dihydroquinoline-1 (2H)-yl] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 151b, carry out the operation same, obtain the title compound (yield 55%) of colorless solid with embodiment 36c.185～193 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.67 (1H, d, J=7.5), 7.56-7.61 (2H, m), 7.45-7.52 (1H, m), 7.14-7.27 (3H, m), 6.99 (1H, t, J=7.2), (6.56 2H, s, fumaric acid), 4.48 (2H, s), 3.89 (2H, t, J=7.2), 3.41 (2H, d, J=7.2), 2.94-3.02 (2H, m), 2.84 (2H, t, J=7.6), 2.4-2.6 (4H, m), 2.0-2.2 (2H, m), 1.5-1.9 (5H, m), 1.1-1.3 (2H, m)
Embodiment 152:2-[[1-[3-[2-Oxoquinoline-1 (2H)-yl] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate (compound 606 of table 1)
A) 1-(3-hydroxypropyl) quinoline-2 (1H)-ketone
Use the 2-hydroxyquinoline, carry out the operation same, obtain the title compound (yield 41%) of colorless solid with embodiment 151a.
1H-NMR(CDCl 3)：7.76(1H，d，J＝9.5)，7.57-7.64(2H，m)，7.46(1H，d，J＝8.9)，7.25-7.32(1H，m)，6.75(1H，d，J＝9.5)，4.51(2H，t，J＝6.0)，3.6-4.4(1H，broad，OH)，3.51(2H，t，J＝5.5)，1.97-2.07(2H，m)
B) 2-[[1-[3-[2-Oxoquinoline-1 (2H)-yl] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 152a, carry out the operation same, obtain crude product 1-(3-hydroxypropyl) quinoline-2 (1H)-ketone methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 88%) of yellow oil with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.2)，7.66(1H，d，J＝9.5)，7.42-7.58(6H，m)，7.15-7.27(2H，m)，6.68(1H，d，J＝9.5)，4.40(2H，s)，4.34(2H，t，J＝7.4)，3.52(2H，d，J＝7.2)，2.90-2.98(2H，m)，2.46(2H，t，J＝6.9)，2.0-2.2(2H，m)，1.6-2.0(7H，m)，1.3-1.5(2H，m)
C) 2-[[1-[3-[2-Oxoquinoline-1 (2H)-yl] propyl group] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 152b, carry out the operation same, obtain the title compound (yield 82%) of colorless solid with embodiment 36c.208～215 ℃ of fusing points
1H-NMR (DMSO-d 6): 7.90 (1H, d, J=9.5), 7.57-7.74 (6H, m), 7.45-7.52 (1H, m), 7.22-7.31 (1H, m), 6.60 (1H, d, J=9.5), (6.57 2H, s, fumaric acid), 4.48 (2H, s), 4.25 (2H, t, J=7.2), 3.42 (2H, d, J=7.1), 2.95-3.03 (2H, m), 2.57 (2H, t, J=6.9), 2.06-2.18 (2H, m), 1.7-1.9 (3H, m), 1.5-1.6 (2H, m), 1.2-1.4 (2H, m)
Embodiment 153:2-[[1-[2-(2-oxo-3-phenylimidazolidines,-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 596 of table 1)
A) 1-(2-hydroxyethyl)-3-phenylimidazolidines,-2-ketone
Use is according to document (" organic chemistry magazine " (J.Org.Chem.) 1951,16,1829) the t-butyldimethylsilyl 2-bromotrifluoromethane ether that obtains in 1-phenylimidazolidines,-2-ketone that method obtains and the method for embodiment 92a, carry out the operation same, obtain crude product 1-[2-(t-butyldimethylsilyloxy base) ethyl with embodiment 151a]-3-phenylimidazolidines,-2-ketone.Carry out the operation same with it, obtain the title compound (yield 75%) of colorless solid with embodiment 92b.
1H-NMR(CDCl 3)：7.53(2H，d，J＝8.0)，7.34(2H，t，J＝8.4)，7.05(1H，t，J＝7.4)，3.82-3.89(4H，m)，3.59(2H，t，J＝7.3)，3.45(2H，t，J＝5.1)，3.01(1H，brs，OH)
B) 2-[[1-[2-(2-oxo-3-phenylimidazolidines,-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 153a, carry out the operation same, obtain crude product 1-(2-hydroxyethyl)-3-phenylimidazolidines,-2-ketone methanesulfonates with embodiment 26a.Carry out the operation same with it, obtain the title compound (yield 65%) of colorless oil with embodiment 26b.
1H-NMR(CDCl 3)：7.85(1H，d，J＝7.5)，7.41-7.57(5H，m)，7.32(2H，t，J＝7.5)，7.02(1H，t，J＝7.5)，4.40(2H，s)，3.77-3.84(2H，m)，3.53-3.60(2H，m)，3.50(2H，d，J＝7.2)，3.42(2H，t，J＝6.3)，2.93-3.02(2H，m)，2.55(2H，t，J＝6.6)，1.95-2.07(2H，m)，1.5-1.8(3H，m)，1.2-1.4(2H，m)
C) 2-[[1-[2-(2-oxo-3-phenylimidazolidines,-1-yl) ethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 153b, carry out the operation same, obtain the title compound (yield 93%) of colorless solid with embodiment 1f.207～219 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.6-10.0(1H，broad，HCl)，7.68(1H，d，J＝7.5)，7.45-7.62(5H，m)，7.33(2H，t，J＝7.8)，7.01(1H，t，J＝7.4)，4.51(2H，s)，3.80-3.88(2H，m)，3.50-3.62(6H，m)，3.43(2H，d，J＝7.5)，3.27(2H，t，J＝5.9)，2.80-3.0(2H，m)，1.9-2.1(1H，m)，1.6-1.8(2H，m)，1.4-1.6(2H，m)
Embodiment 154:5-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 9 of table 1)
A) 4-fluoro-2-tolyl acid ethyl ester
(0.644g, 26.5mmol) middle THF 4mL and a spot of iodine of adding after the stirring, splashes into 1-bromo-4-fluoro-2-toluene (5.00g, THF 26.5mmol) (50mL) solution to magnesium.After at room temperature stirring 30 minutes, (3.80mL in THF 39.8mmol) (40mL) solution, slowly is warming up to room temperature then to splash into the chloro ethyl formate that is cooled to-78 ℃.After at room temperature stirring 2 hours, use the ether dilute reaction solution, dried over sodium sulfate is used in water, saturated sodium bicarbonate water, saturated common salt water washing.The filtering siccative, after concentrating that the oily mater that obtains is refining with silica gel column chromatography (hexane/ether), obtain title compound 3.65g (yield 76%).
1H-NMR(CDCl 3)：δ1.39(t，J＝7.0Hz，3H)，2.61(s，3H)，4.35(q，J＝7.0Hz，2H)，6.89-6.95(m，2H)，7.95(m，1H).
B) 4-(5-fluoro-1-oxo isoindole is expired-the 2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
Use the compound that obtains among the embodiment 154a, carry out the operation same, obtain title compound (yield 57%) with embodiment 1b, 1c.
1H-NMR(CDCl 3)：δ1.25(m，2H)，1.45(s，9H)，1.64(m，2H)，1.93(m，1H)，2.69(m，2H)，3.47(m，2H)，4.11(m，2H)，4.39(s，2H)，7.12-7.20(m，2H)，7.82(dd，J＝5.0，8.3Hz，1H).
C) 5-fluoro-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 154b, carry out the operation same, obtain title compound (yield 91%) with embodiment 1d.
1H-NMR(DMSO-d 6)：δ1.36(m，2H)，1.73(m，2H)，2.00(m，1H)，2.80(m，2H)，3.24(m，2H)，3.42(d，J＝7.5Hz，2H)，4.49(s，2H)，7.32(m，1H)，7.49(d，J＝8.6Hz，1H)，7.71(dd，J＝5.1，8.4Hz，1H)，8.49(br s，1H)，8.78(br s，1H).
D) 5-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 154c, carry out the operation same, obtain title compound (yield 85%) with embodiment 1e.
1H-NMR(CDCl 3)：δ1.47(m，2H)，1.68(m，2H)，1.81(m，1H)，2.15(m，2H)，2.96(m，2H)，3.49(d，J＝7.2Hz，2H)，3.72(s，2H)，4.38(s，2H)，7.08-7.18(m，4H)，7.81(dd，J＝5.0，8.3Hz，1H)，8.07(m，2H).
E) 5-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 154d, carry out the operation same, obtain title compound (yield 90%) with embodiment 1f.209～216 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.58-1.86(m，4H)，2.03(m，1H)，3.04(m，2H)，3.45(d，J＝8.8Hz，2H)，3.54(m，2H)，4.53(s，2H)，5.04-5.10(m，2H)，7.33(m，1H)，7.45-7.53(m，3H)，7.73(dd，J＝5.2，8.3Hz，1H)，8.06-8.15(m，2H)，9.96(br s，1H).
Embodiment 155:6-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound 18 of table 1)
A) 3-hydroxy-2-methylbenzoic acid methyl esters
Use the 3-hydroxy-2-methylbenzoic acid, carry out the operation same, obtain title compound (yield 97%) with embodiment 3a.
1H-NMR(CDCl 3)：δ2.46(s，3H)，3.89(s，3H)，6.94(d，J＝8.3Hz，1H)，7.11(t，J＝8.3Hz，1H)，7.42(d，J＝8.3Hz，1H).
B) 3-(tertiary butyl-dimethyl-silicon alkoxyl group [シ ラ ニ Le オ キ シ])-2-methyl-toluate
With the compound (4.99g that obtains among the embodiment 155a, 30.0mmol) be dissolved among the DMF of 26mL, add TERT-BUTYL DIMETHYL CHLORO SILANE (5.43g, 36.0mmol), imidazoles (5.11g, 75.0mmol), after at room temperature stirring, saturated sodium bicarbonate water is added in the reaction solution, with hexane extraction 4 times, with the organic layer dried over sodium sulfate that merges.The filtering siccative, after concentrating that the oily mater that obtains is refining with silica gel column chromatography (hexane/ethyl acetate), obtain title compound 8.24g (yield 93%).
1H-NMR(CDCl 3)：δ0.21(s，6H)，1.02(s，9H)，2.41(s，3H)，3.88(s，3H)，6.93(d，J＝8.4Hz，1H)，7.09(t，J＝8.4Hz，1H)，7.42(d，J＝8.4Hz，1H).
C) 4-[6-(tertiary butyl-dimethyl-silicon alkoxyl group)-1-oxo isoindole is expired-the 2-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
Use the compound that obtains among the embodiment 155b, carry out the operation same, obtain title compound (yield 71%) with embodiment 1b, 1c.
1H-NMR(CDCl 3)：δ0.25(s，6H)，1.02(s，9H)，1.26(m，2H)，1.45(s，9H)，1.66(m，2H)，1.95(m，1H)，2.70(m，2H)，3.49(m，2H)，4.10(m，2H)，4.30(s，2H)，6.93(d，J＝7.7Hz，1H)，7.33(t，J＝7.7Hz，1H)，7.45(d，J＝7.7Hz，1H).
D) 4-(6-hydroxyl-1-oxo isoindole is expired-the 2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester
With the compound that obtains among the embodiment 155c (9.20g, 20.0mmol) and acetic acid 9.44mL be dissolved among the THF of 100mL, be cooled to 0 ℃, splash into 1M tetrabutylammonium fluoride/THF solution (20.0mL, 20.0mmol).After 30 minutes, reaction solution is diluted with vinyl acetic monomer,, use dried over sodium sulfate with 0.5N aqueous hydrochloric acid * 3, saturated common salt water washing.The filtering siccative, after concentrating, the oily mater methylene dichloride/ether/hexane partial crystallization with obtaining obtains title compound 5.70g (yield 82%).
1H-NMR(CDCl 3)：δ1.23(m，2H)，1.46(s，9H)，1.65(m，2H)，1.95(m，1H)，2.69(m，2H)，3.50(m，2H)，4.12(m，2H)，4.41(s，2H)，7.03(d，J＝7.5Hz，1H)，7.29(t，J＝7.5Hz，1H)，7.39(d，J＝7.5Hz，1H).
E) 6-methoxyl group-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
The compound that in embodiment 155d, obtains (0.600g, add in acetonitrile 1.74mmol) (6mL) solution methyl iodide (0.216mL, 3.46mmol), (478mg 3.46mmol), is heated to 60 ℃ to salt of wormwood.2.5 after hour, the reaction solution that is cooled to room temperature is diluted with vinyl acetic monomer,, uses dried over sodium sulfate with saturated sodium bicarbonate water * 2, saturated common salt water washing.The filtering siccative, after concentrating, the crude product of acquisition obtains title compound (yield 94%) without carry out the operation same with embodiment 1d refiningly.
1H-NMR(DMSO-d 6)：δ1.36(m，2H)，1.71(m，2H)，2.04(m，1H)，2.79(m，2H)，3.24(m，2H)，3.42(d，J＝7.4Hz，2H)，3.89(s，3H)，4.41(s，2H)，7.21(d，J＝8.1Hz，1H)，7.26(d，J＝7.4Hz，1H)，7.47(dd，J＝7.4，8.1Hz；1H)，8.55(br s，1H)，8.84(br s，1H).
F) 6-methoxyl group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 155e, carry out the operation same, obtain title compound (yield 67%) with embodiment 1e, 1f.213～229 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.57-1.84(m，4H)，2.05(m，1H)，3.02(m，2H)，3.45(d，J＝6.9Hz，2H)，3.53(m，2H)，3.89(s，3H)，4.45(s，2H)，5.03-5.09(m，2H)，7.22(d，J＝8.1Hz，1H)，7.27(d，J＝7.4Hz，1H)，7.45-7.50(m，3H)，8.05-8.15(m，2H)，9.95(br s，1H).
Embodiment 156:6-oxyethyl group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
A) 6-oxyethyl group-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 155d, carry out the operation same, obtain title compound (yield 97%) with 155e.
1H-NMR(DMSO-d 6)：δ1.36(m，2H)，1.37(t，J＝6.9H2，3H)，1.71(m，2H)，2.05(m，1H)，2.79(m，2H)，3.23(m，2H)，3.42(d，J＝7.1Hz，2H)，4.16(q，J＝6.9Hz，2H)，4.41(s，2H)，7.19(d，J＝8.1Hz，1H)，7.25(d，J＝7.4Hz，1H)，7.45(dd，J＝7.4，8.1Hz，1H)，8.74(br s，1H)，9.02(br s，1H).
B) 6-oxyethyl group-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 156a, carry out the operation same, obtain title compound (yield 43%) with embodiment 1e, 1f.200～209 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.37(t，J＝6.9Hz，3H)，1.57-1.84(m，4H)，2.08(m，1H)，3.01(m，2H)，3.45(d，J＝6.8Hz，2H)，3.53(m，2H)，4.17(q，J＝6.9Hz，2H)，4.44(s，2H)，5.03-5.09(m，2H)，7.20(d，J＝8.0Hz，1H)，7.26(d，J＝7.4Hz，1H)，7.42-7.50(m，3H)，8.06-8.16(m，2H)，9.93(br s，1H).
Embodiment 157:6-isopropoxy-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride
A) 6-isopropoxy-2-(piperidin-4-yl methyl) isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 155d, carry out the operation same, obtain title compound (yield 99%) with 155e.
1H-NMR(DMSO-d 6)：δ1.30(d，J＝5.5Hz，6H)，1.34(m，2H)，1.71(m，2H)，2.04(m，1H)，2.79(m，2H)，3.23(m，2H)，3.41(d，J＝6.6Hz，2H)，4.37(s，2H)，4.74(m，1H)，7.21-7.23(m，2H)，7.43(m，1H)，8.60(br s，1H)，8.88(br s，1H).
B) 6-isopropoxy-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 157a, carry out the operation same, obtain title compound (yield 53%) with embodiment 1e, 36c.132 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.21(m，2H)，1.30(d，J＝6.0Hz，6H)，1.55(m，2H)，1.76(m，1H)，2.13(m，2H)，2.87(m，2H)，3.38(d，J＝7.2Hz，2H)，3.81(s，2H)，4.35(s，2H)，4.74(m，1H)，6.61(s，2H)，7.19-7.23(m，2H)，7.35(t，J＝8.7Hz，2H)，7.42(t，J＝7.8Hz，1H)，8.09(dd，J＝5.7，8.7Hz，2H).
Embodiment 158:5-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-4,5-dihydro-6H furo[Off ロ] [2,3-c] pyrroles-6-ketone fumarate (compound 817 of table 2)
A) 3-brooethyl furans-2-carboxylate methyl ester
(2.00g 14.27mmol), carries out the reaction same with embodiment 1c, obtains the crude product 3.51g of the title compound of yellow oil to use 3-methyl furan-2-carboxylate methyl ester.The crude product that obtains is directly used in following reaction without making with extra care.
B) 3-[[1-(tertbutyloxycarbonyl) piperidin-4-yl] the methylamino methyl]-the pyromucic acid methyl esters
Use the compound 3.51g that obtains among the embodiment 158a, carry out the reaction same, obtain the title compound 1.80g (yield 36%, 2 step) of yellow oil with embodiment 1c.
1H-NMR(CDCl 3)：7.48(1H，d，J＝1.5Hz)，6.55(1H，d，J＝1.8Hz)，4.09(2H，brd，J＝11.7Hz)，3.94-3.91(5H，m)，2.69((2H，brt，J＝12.5Hz)，2.51(2H，d，J＝6.6Hz)，1.73-1.58(3H，m)，1.45(9H，s)，1.18-1.06(2H，m).
C) 3-[[1-(tertbutyloxycarbonyl) piperidin-4-yl] the methylamino methyl]-pyromucic acid
Use the compound 1.80g that obtains among the embodiment 158b, carry out the reaction same, obtain yellow semisolid title compound 1.35g (yield 78%) with embodiment 22d.
1H-NMR(CDCl 3)：10.36(2H，brs)，7.48(1H，d，J＝1.5Hz)，6.58(1H，d，J＝1.2Hz)，4.23(2H，brs)，4.09(2H，brd，J＝7.4Hz)，2.97-2.70(4H，m)，2.08(1H，brs)，1.85(2H，brd，J＝12.0Hz)，1.42(9H，s)，1.25-1.11(2H，m).
D) 4-[(4,5-dihydro-6H-Off ロ [2,3-c] pyrroles-6-ketone)-the 2-ylmethyl] piperidines-1-carboxylic acid tert-butyl ester
With the compound that obtains among the embodiment 158c (658mg, 1.94mmol), 2,2 '-pyridyl disulfide (513mg, 2.33mmol), (611mg 2.33mmol) is dissolved in the acetonitrile (6ml) reflux 4 hours to triphenylphosphine.With reaction solution put cold after, distillation removes desolvates, and adds entry, uses ethyl acetate extraction.Organic layer washs in turn with saturated sodium bicarbonate aqueous solution, water, saturated aqueous common salt, uses anhydrous sodium sulfate drying.After filtering out dud, decompression is distilled down to remove and is desolvated, and the crude product that obtains is refining with silica gel column chromatography (vinyl acetic monomer/hexane=1/1), the title compound (694mg is with the mixture of reagent) of acquisition yellow oil.
E) 5-(piperidin-4-yl methyl)-4,5-dihydro-6H-Off ロ [2,3-c] pyrroles-6-keto hydrochloride
Use the compound 658mg that obtains among the embodiment 158d, carry out the reaction same, obtain the title compound 161mg (yield 12%, 3 step) of colorless solid with embodiment 1d.
1H-NMR(DMSO-d 6)：8.92(1H，brs)，8.65(1H，brs)，7.99(1H，s)，6.77(1H，s)，4.30(2H，s)，3.33(1H，d，J＝7.4Hz)，3.24(1H，brd，J＝12.7Hz)，2.79(2H，brdd，J＝23.2，12.0Hz)，1.99-1.91(1H，m)，1.72(2H，d，J＝13.2Hz)，1.42-1.29(2H，m).
F) 5-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl]-4,5-dihydro-6H Off ロ [2,3-c] pyrroles-6-ketone
Use the compound 80mg (0.312mmol) that obtains among the embodiment 158e, carry out the reaction same, obtain the title compound 90mg (yield 81%) of colorless solid with embodiment 1e.
1H-NMR(CDCl 3)：8.10-8.05(2H，m)，7.61(1H，d，J＝1.7Hz)，7.12(2H，t，J＝8.7Hz)，6.50(1H，d，J＝1.6Hz)，4.18(2H，s)，3.72(2H，s)，3.41(2H，d，J＝7.2Hz)，2.96(2H，brd，J＝11.4Hz)，2.18-2.10(2H，m)，1.78-1.62(3H，m)，1.50-1.41(2H，m).
G) 4-fluoro-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate
Use the compound 90mg (0.253mmol) that obtains among the embodiment 158f, carry out the reaction same, obtain the title compound 109mg (yield 91%) of colorless solid with embodiment 36c.230～232 ℃ of fusing points
1H-NMR((DMSO-d 6)：8.11-8.07(2H，m)，7.97(1H，d，J＝1.7Hz)，7.38-7.32(2H，m)，6.75(1H，d，J＝1.6Hz)，6.61(2H，s)，4.27(2H，s)，3.84(2H，s)，3.29(2H，d，J＝7.2Hz)，2.88(2H，brd，J＝11.4Hz)，2.14(2H，t，J＝10.8Hz)，1.70-1.67(1H，m)，1.56(2H，d，J＝12.3Hz)，1.26-1.16(2H，m).
Embodiment 159:5-methoxyl group-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 204 of table 1)
Use the compound that obtains among the embodiment 8c, carry out the operation same, obtain title compound with embodiment 26b, 36c.178～180 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.26(m，2H)，1.63(m，2H)，1.79(m，1H)，2.25(m，2H)，2.72(m，2H)，2.78(m，2H)，3.08(m，2H)，3.38(d，J＝7.1Hz，2H)，3.83(s，3H)，4.42(s，2H)，6.57(s，2H)，7.00-7.14(m，4H)，7.27(m，2H)，7.57(d，J＝8.4Hz，1H).
Embodiment 160:5-bromo-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 198 of table 1)
Use the compound that obtains among the embodiment 3d, carry out the operation same, obtain title compound with embodiment 26b, 36c.203～219 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.26(m，2H)，1.62(m，2H)，1.79(m，1H)，2.20(m，2H)，2.69(m，2H)，2.77(m，2H)，3.05(m，2H)，3.40(d，J＝7.0Hz，2H)，4.49(s，2H)，6.58(s，2H)，7.10(t，J＝8，6Hz，2H)，7.24-7.29(m，2H)，7.59(m，2H)，7.86(s，1H).
Embodiment 161:5-chloro-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 203 of table 1)
A) 5-chloro-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 9c (250mg, 0.83mmol) and the compound that obtains among the embodiment 26a (181mg 0.83mmol), carries out the reaction same with embodiment 26b, obtains the crude product 245mg of filbert solid title compound.The crude product that obtains is directly used in following reaction without making with extra care.
B) 5-chloro-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline～1-ketone fumarate
Use the compound 240mg that obtains among the embodiment 161a, carry out the reaction same, obtain the title compound 299mg (yield 72%, 2 step) of colorless solid with embodiment 36c.220～229 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.69(2H，t，J＝7.7Hz)，7.54(1H，dd，J＝7.9，1.4Hz)，7.27(2H，dd，J＝8.4，5.7Hz)，7.10(2H，t，J＝8.9Hz)，6.57(2H，s)，4.49(2H，s)，3.41(2H，d，J＝7.2Hz)，3.10(2H，brd，J＝11.6Hz)，2.82-2.70(4H，m)，2.26(2H，brt，J＝11.0Hz)，1.83-1.77(1H，m)，1.64(2H，brd，J＝11.7Hz)，1.32-1.24(2H，m).
Embodiment 162:5-cyano group-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 205 of table 1)
A) 5-cyano group-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 10c (300mg, 1.03mmol) and the compound that obtains among the embodiment 26a (225mg 1.03mmol), carries out the reaction same with embodiment 26b, obtains the crude product 224mg of filbert solid title compound.The crude product that obtains is directly used in following reaction without making with extra care.
B) 5-cyano group-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate
Use the compound 224mg that obtains among the embodiment 162a, carry out the reaction same, obtain the title compound 258mg (yield 50%, 2 step) of colorless solid with embodiment 36c.201～208 ℃ of fusing points
1H-NMR(DMSO-d 6)：8.13(1H，s)，7.96(1H，d，J＝7.9Hz)，7.85(1H，d，J＝7.7Hz)，7.27(2H，dd，J＝8.4，5.7Hz)，6.57(2H，s)，4.57(2H，s)，3.45(2H，d，J＝7.3Hz)，3.08(2H，brd，J＝11.5Hz)，2.82-2.68(4H，m)，2.23(2H，brt，J＝11.1Hz)，1.29(2H，brdd，J＝21.7，11.4Hz).
Embodiment 163:5-fluoro-2-[[1-[2-(4-fluorophenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 154c, carry out the operation same, obtain title compound (yield 72%) with embodiment 26b, 36c.197～204 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.26(m，2H)，1.62(m，2H)，1.76(m，1H)，2.16(m，2H)，2.66(m，2H)，2.78(m，2H)，3.03(m，2H)，3.40(d，J＝7.2Hz，2H)，4.48(s，2H)，6.58(s，2H)，7.10(t，J＝9.0Hz，2H)，7.24-7.35(m，3H)，7.46(dd，J＝2.0，8.9Hz，1H)，7.71(dd，J＝5.1，8.4Hz，1H).
Embodiment 164:4-fluoro-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 202 of table 1)
A) 4-fluoro-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 6d (500mg, 1.76mmol) and the compound that obtains among the embodiment 26a (384mg 1.76mmol), carries out the reaction same with embodiment 26b, obtains the crude product 478mg of the title compound of colorless oil.The crude product that obtains is directly used in following reaction without making with extra care.
B) 4-fluoro-2-[1-[2-(4-fluorophenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate
Use the compound 478mg that obtains among the embodiment 164a, carry out the reaction same, obtain the title compound 560mg (yield 89%, 2 step) of colorless solid with embodiment 36c.230～232 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.57-7.53(2H，m)，7.47-7.42(1H，m)，7.26(2H，dd，J＝8.6，5.7Hz)，7.12-7.06(2H，m)，6.58(2H，s)，4.58(2H，s)，3.42(2H，d，J＝7.3Hz)，3.02(2H，brd，J＝brd，J＝11.9Hz)，2.79-2.74(2H，m)，2.66-2.61(2H，m)，2.14(2H，brt，J＝11.6Hz)，1.81(1H，brs)，1.63(2H，brd，J＝13.1Hz)，1.27-1.20(2H，m).
Embodiment 165:2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl]-5-methoxyl group isoindoline-1-keto hydrochloride (compound 154 of table 1)
A) 2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl]-5-methoxyl group isoindoline-1-ketone
In the presence of yellow soda ash (233mg), sodium iodide (165mg), make the compound (297mg that obtains among the embodiment 9c, 1mmol) (230mg, 1mmol) at N, reaction is 8 hours in the dinethylformamide, under 80 ℃ with 1-methoxyl group-2-(2-mesyloxy) ethylbenzene.Add entry in reaction solution, use ethyl acetate extraction, after the washing, underpressure distillation removes and desolvates.The oily matter that obtains is refining with silica gel column chromatography (methylene chloride-methanol), obtain title compound.
1H-NMR(CDCl 3)：7.75(d，J＝8.4Hz，1H)，7.15(m，2H)，6.99-6.81(m，3H)，4.35(s，2H)，3.86(s，3H)，3.80(s，3H)，3.47(d，J＝7.1Hz，2H)，3.03(brd，J＝11.5Hz，2H)，2.85-2.79(m，2H)，2.58-2.52(m，2H)，2.04(t，J＝10.0Hz)，1.80(m，1H)，1.74-1.68(m，2H)，1.50-1.39(m，2H)
B) 2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl]-5-methoxyl group isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 165a, carry out the operation same, obtain title compound (yield 46%) with embodiment 1f.204～207 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.12(brs，1H)，7.58(d，J＝8.4Hz)，7.28-7.17(m，3H)，7.05-6.89(m，3H)，4.45(s，2H)，3.84(s，3H)，3.80(s，3H)，3.57-3.53(m，2H)，3.41(d，J＝7.2Hz)，3.20-3.12(m，2H)，3.02-2.88(m ，4H)，1.98(m，1H)，1.83-1.78(m，2H)，1.56-1.51(m，2H)
Embodiment 166:5-chloro-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone 3/2 fumarate (compound 153 of table 1)
A) 5-chloro-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 8e (250mg, 0.83mmol) and the compound that obtains among the embodiment 26a (191mg 0.83mmol), carries out the reaction same with embodiment 26b, obtains the crude product 270mg of filbert solid title compound.The crude product that obtains is directly used in following reaction without making with extra care.
B) 5-chloro-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone 1.5 fumarates
Use the compound 270mg that obtains among the embodiment 166a, carry out the reaction same, obtain the title compound 269mg (yield 60%, 2 step) of colorless solid with embodiment 36c.165～185 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.69(2H，t，J＝7.5Hz)，7.54(1H，dd，J＝8.1，1.5Hz)，7.23-7.14(2H，m)，6.96(1H，d，J＝7.8Hz)，6.87(1H，d，J＝7.5Hz)，6.57(3H，s)，4.50(2H，s)，3.78(2H，s)，3.42(2H，d，J＝7.2Hz)，3.20(2H，brd，J＝12.0Hz)，2.81(2H，brs)，2.43(2H，brt，J＝11.1Hz)，1.86(1H，brs)，1.69(2H，brd，J＝11.4Hz)，1.36(2H，brdd，J＝22.5，10.8Hz).
Embodiment 167:2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl]-5-bromine isoindoline-1-keto hydrochloride (compound 148 of table 1)
A) 2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl]-5-bromine isoindoline-1-ketone
Use the compound that obtains among the embodiment 3d, carry out the operation same, obtain title compound (yield 43%) with embodiment 165a.
1H-NMR(CDCl 3)：7.70(d，J＝8.4Hz)，7.59(m，2H)，7.17-7.11(m，2H)，6.89-6.81(m，2H)，4.38(s，2H)，3.80(s，3H)，3.49(d，J＝7.1Hz，2H)，3.02(brd，J＝11.7Hz，2H)，2.85-2.79(m，2H)，2.58-2.52(m，2H)，2.04(t，J＝11.6Hz)，1.82(m，1H)，1.73-1.68(m，2H)，1.47-1.41(m，2H)
B) 2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl]-5-bromine isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 167a, carry out the operation same, obtain title compound (yield 81%) with embodiment 1f.240～245 ℃ of fusing points
Embodiment 168:5-cyano group-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 155 of table 1)
A) 5-cyano group-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 10c (300mg, 1.03mmol) and the compound that obtains among the embodiment 26a (237mg 1.03mmol), carries out the reaction same with embodiment 26b, obtains the crude product 174mg of filbert solid title compound.The crude product that obtains is directly used in following reaction without making with extra care.
B) 5-cyano group-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate
Use the compound 174mg that obtains among the embodiment 168a, carry out the reaction same, obtain the title compound 202mg (yield 39%, 2 step) of colorless solid with embodiment 36c.201～208 ℃ of fusing points
1H-NMR(DMSO-d 6)：8.14(1H，s)，7.96(1H，d，J＝8.1Hz)，7.85(1H，d，J＝7.5Hz)，7.22-7.14(2H，m)，6.95(1H，d，J＝8.1Hz)，6.86(1H，t，J＝7.5Hz)，6.57(2H，s)，4.57(2H，s)，3.77(3H，s)，3.45(2H，d，J＝7.2Hz)，3.09(2H，brd，J＝10.8Hz)，2.80-2.75(2H，m)，2.66(2H，brd，J＝8.7Hz)，2.24(2H，brt，J＝11.0Hz)，1.82(1H，brs)，1.65(2H，bed，J＝12.0H)，1.29(2H，brdd，J＝21.8，11.6Hz).
Embodiment 169:5-fluoro-2-[[1-[2-(2-p-methoxy-phenyl) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 154c, carry out the operation same, obtain title compound (yield 69%) with embodiment 26b, 36c.210～216 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.30(m，2H)，1.65(m，2H)，1.76(m，1H)，2.27(m，2H)，2.68(m，2H)，2.77(m，2H)，3.10(m，2H)，3.41(d，J＝7.2Hz，2H)，3.77(s，3H)，4.49(s，2H)，6.56(s，2H)，6.87(t，J＝7.4Hz，1H)，6.95(d，J＝8.1Hz，1H)，7.14-7.22(m，2H)，7.32(m，1H)，7.47(dd，J＝2.1，8.7Hz，1H)，7.71(dd，J＝5.3，8.3Hz，1H).
Embodiment 170:5-cyano group-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 152 of table 1)
A) 5-cyano group-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 10c (300mg, 1.05mmol) and the compound that obtains among the embodiment 26a (242mg 1.05mmol), carries out the reaction same with embodiment 26b, obtains the crude product 308mg of filbert solid title compound.The crude product that obtains is directly used in following reaction without making with extra care.
B) 5-cyano group-2-[1-[2-(2-p-methoxy-phenyl) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate
Use the compound 308mg that obtains among the embodiment 170a, carry out the reaction same, obtain the title compound 346mg (yield 86%, 2 step) of colorless solid with embodiment 36c.242～247 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.57-7.54(2H，m)，7.47-7.42(1H，m)，7.22-7.14(1H，m)，6.95(1H，d，J＝7.6Hz)，6.89-6.87(1H，m)，6.56(2H，s)，4.58(2H，s)，3.78(3H，s)，3.43(2H，d，J＝7.3Hz)，3.13(2H，brd，J＝11.8Hz)，2.82-2.68(4H，m)，2.32(2H，brt，J＝11.0Hz)，1.86(1H，brs)，1.67(2H，brd，J＝11.1Hz)，1.38-1.27(2H，m).
Embodiment 171:(R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-4-fluorine isoindoline-1-keto hydrochloride (compound 83 of table 1)
A) (R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-4-fluorine isoindoline-1-ketone
Use the compound that obtains among the embodiment 6, carry out the operation same, obtain title compound (yield 85%) with embodiment 16a.
1H-NMR(CDCl 3)：7.66(d，J＝7.8Hz，1H)，7.46(m，1H)，7.35-7.30(m，2H)，7.22(t，J＝8.1Hz，1H)，7.04-6.99(m，2H)，4.71-4.66(m，1H)，4.46(s，2H)，3.53(d，J＝7.2Hz，2H)，3.15(brd，J＝11.7Hz，1H)，2.82(brd，J＝10.2Hz，1H)，2.51-2.31(m，3H)，2.04(m，1H)，1.85(m，1H)，1.80-1.65(m，2H)，1.49-1.22(m，2H)
B) (R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-4-fluorine isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 171a, carry out the operation same, obtain title compound (yield 78%) with embodiment 1f.221～224 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.63(brs，1H)，7.56-7.42(m，5H)，7.20(t，J＝8.7Hz，2H)，6.24(brs，1H)，5.11(brs，1H)，4.59(s，2H)，3.55-2.90(m，8H)，2.00(m，1H)，1.86-1.56(m，4H)
Embodiment 172:(R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-chlorine isoindoline-1-keto hydrochloride (compound 84 of table 1)
A) (R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-chlorine isoindoline-1-ketone
Use the compound that obtains among the embodiment 8, carry out the operation same, obtain title compound (yield 82%) with embodiment 16a.
1H-NMR(CDCl 3)：7.78(d，J＝8.7Hz，1H)，7.44(m，2H)，7.35-7.30(m，2H)，7.02(m，2H)，4.69(m，1H)，4.44(s，2H)，4.09(brs，1H)，3.51(d，J＝7.2Hz，2H)，3.15(brd，J＝11.4Hz，1H)，2.81(brd，J＝11.1Hz，1H)，2.49-2.30(m，3H)，2.02(m，1H)，1.80(m，1H)，1.80-1.20(m，4H)
B) (R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-chlorine isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 172a, carry out the operation same, obtain title compound (yield 90%) with embodiment 1f.254～256 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.59(brs，1H)，7.74-7.67(m，2H)，7.56-7.43(m，3H)，7.25-7.20(m，2H)，6.27(brs，1H)，5.13(brs，1H)，4.52(s，2H)，3.64-2.95(m，8H)，1.99-1.57(m，5H)
Embodiment 173:(R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-fluorine isoindoline-1-keto hydrochloride
A) (R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-fluorine isoindoline-1-ketone
Use the compound that obtains among the embodiment 154, carry out the operation same, obtain title compound (yield 61%) with embodiment 16a.
1H-NMR(CDCl 3)：7.83(m，1H)，7.35-7.25(m，2H)，7.17-7.12(m，2H)，7.05-6.99(m，2H)，4.67(m，1H)，4.44(s，2H)，4.08(brs，1H)，3.51(d，J＝7.2Hz，2H)，3.15(brd，J＝11.1Hz，1H)，2.82(brs，J＝11.1Hz，1H)，2.49-2.28(m，3H)，2.02(m，1H)，1.80(m，1H)，1.77-1.25(m，4H)
B) (R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-fluorine isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 173a, carry out the operation same, obtain title compound (yield 70%) with embodiment 1f.243～245 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.66(brs，1H)，7.71(m，1H)，7.43(m，3H)，7.34-7.17(m，3H)，6.24(d，J＝3.9Hz，1H)，5.11(brs，1H)，4.49(s，2H)，3.66-2.91(m，8H)，1.97-1.52(m，5H)
Embodiment 174:(R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-cyano group isoindoline-1-keto hydrochloride (compound 87 of table 1)
A) (R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-cyano group isoindoline-1-ketone
Use the compound that obtains among the embodiment 10, carry out the operation same, obtain title compound (yield 37%) with embodiment 16a.
1H-NMR(CDCl 3)：7.95(d，J＝7.8Hz，1H)，7.76(m，2H)，7.32(m，2H)，7.01(m，2H)，4.69(m，1H)，4.47(s，2H)，3.55(d，J＝7.2Hz，2H)，3.14(brd，J＝10.5Hz，1H)，2.81(brd，J＝10.5Hz，1H)，2.79-2.29(m，3H)，2.03(m，1H)，1.95-1.35(m，5H)
B) (R, S)-2-[1-[2-(4-fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-5-cyano group isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 174a, carry out the operation same, obtain title compound (yield 74%) with embodiment 1f.255～262 ℃ of fusing points
1H-NMR(DMSO-d 6)：9.66(brs，1H)，8.16(s，1H)，7.96(d，J＝7.5Hz，1H)，7.86(d，J＝7.8Hz，1H)，7.45(m，2H)，7.22(m，2H)，6.27(brs，1H)，5.13(brs，1H)，4.59(s，2H)，3.60-2.92(m，8H)，1.98-1.54(m，5H)
Embodiment 175:(R, S)-5-[1-[2-(fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-4,5-dihydro-6H-thieno-[2,3-c] pyrroles-6-ketone. fumarate (compound 780 of table 2)
A) (R, S)-5-[1-[2-(fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-4,5-dihydro-6H-thieno-[2,3-c] pyrroles-6-ketone
Use the compound that obtains among the embodiment 22, carry out the operation same, obtain title compound (yield 87%) with embodiment 16a.
1H-NMR(CDCl 3)：7.63(d，J＝4.8Hz，1H)，7.32(m，3H)，7.01(m，3H)，4.67(m，1H)，4.34(s，2H)，4.11(brs，1H)，3.47(d，J＝6.9Hz，2H)，3.15(brd，J＝11.1Hz，1H)，2.82(brd，J＝10.8Hz，1H)，2.50-2.30(m，3H)，2.03(m，1H)，1.81-1.71(m，3H)，1.47-1.37(m，1H)
B) (R, S)-5-[1-[2-(fluorophenyl)-2-hydroxyethyl] the piperidin-4-yl methyl]-4,5-dihydro-6H-thieno-[2,3-c] pyrroles-6-ketone fumarate
The compound 70mg that obtains among the embodiment 176a is dissolved in ethanol (1ml), the vinyl acetic monomer (3ml), adds fumaric acid 26mg.Filter and collect the crystallization of separating out after all dissolvings, obtain title compound (yield 87%).174～176 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.95(d，J＝5.1Hz，1H)，7.41-7.35(m，2H)，7.23-7.11(m，3H)，6.57(s，2H)，4.76(brs，1H)，4.42(s，2H)，3.33-2.15(m，8H)，1.72-1.57(m，3H)，1.25-1.15(m，2H)
Embodiment 176:2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl]-5-methoxyl group isoindoline-1-keto hydrochloride (compound 214 of table 1)
A) 2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl]-5-methoxyl group isoindoline-1-ketone
Use the compound and 1-fluoro-4-(2-bromine oxethyl) benzene that obtain among the embodiment 9c, carry out the operation same, obtain title compound (yield 78%) with embodiment 165a.
1H-NMR(CDCl 3)：7.75(d，J＝8.4Hz)，7.00-6.91(m，4H)，6.85-6.80(m，2H)，4.34(s，2H)，4.04(t，J＝6.0Hz，2H)，3.87(s，3H)，3.47(d，J＝7.2Hz，2H)，2.98(brd，J＝11.7Hz，2H)，2.76(t，J＝6.0Hz，2H)，2.09(t，J＝9.3Hz，2H)，1.77(m，1H)，1.72(m，2H)，1.48-1.39(m，2H)
B) 2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl]-5-methoxyl group isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 176a, carry out the operation same, obtain title compound (yield 47%) with embodiment 1f.216～219 ℃ of fusing points
1H-NMR(DMSO-d 6)：10.44(brs，1H)，7.58(d，J＝8.4Hz)，7.19-7.13(m，3H)，7.06-6.99(m，3H)，4.44(s，2H)，4.37(t，J＝4.5Hz，2H)，3.84(s，3H)，3.59-3.45(m，2H)，3.45-3.30(m，4H)，3.05-2.94(m，2H)，1.97(m，1H)，1.81-1.76(m，2H)，1.64-1.52(m，2H)
Embodiment 177:2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl]-5-bromine isoindoline-1-keto hydrochloride (compound 208 of table 1)
A) 2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl]-5-bromine isoindoline-1-ketone
Use the compound and 1-fluoro-4-(2-bromine oxethyl) benzene that obtain among the embodiment 3d, carry out the operation same, obtain title compound (yield 66%) with embodiment 165a.
1H-NMR(CDCl 3)：7.71(d，J＝8.4Hz，1H)，7.62-7.59(m，2H)，6.99-6.93(m，2H)，6.85-6.80(m，2H)，4.38(s，2H)，4.04(t，J＝6.0Hz，2H)，3.48(d，J＝4.9Hz)，2.99(brd，J＝11.7Hz)，2.77(t，J＝6.0Hz)，2.10(t，J＝11.7Hz)，1.80(m，1H)，1.78-1.70(m，2H)，1.48-1.39(m，2H)
B) 2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl]-5-bromine isoindoline-1-keto hydrochloride
Use the compound that obtains among the embodiment 177a, carry out the operation same, obtain title compound (yield 86%) with embodiment 1f.222～225 ℃ of fusing points
Embodiment 178:5-chloro-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 213 of table 1)
A) 5-chloro-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 8e (250mg, 0.83mmol) and the compound that obtains among the embodiment 32a (182mg 0.83mmol), carries out the reaction same with embodiment 26b, obtains the crude product 321mg of filbert solid title compound.The crude product that obtains is directly used in following reaction without making with extra care.
B) 5-chloro-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate
Use the compound 321mg that obtains among the embodiment 178a, carry out the reaction same, obtain the title compound 320mg (yield 74%, 2 step) of colorless solid with embodiment 36c.172～176 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.68(2H，t，J＝7.6Hz)，7.55(1H，d，J＝2.7Hz)，7.11(2H，t，J＝8.8Hz)，6.93-6.79(2H，m)，6.59(2H，s)，4.49(2H，s)，4.08(2H，t，J＝5.6Hz)，3.40(2H，d，J＝7.2Hz)，3.01(2H，brd，J＝11.5Hz)，2.80(2H，t，J＝5.6Hz)，2.21-2.14(2H，m)，1.76-1.72(1H，m)，1.60(2H，brd，J＝12.1Hz)，1.26(2H，brdd，J＝21.4，11.3Hz).
Embodiment 179:5-cyano group-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 215 of table 1)
A) 5-cyano group-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 8e (300mg, 1.03mmol) and the compound that obtains among the embodiment 10c (226mg 1.03mmol), carries out the reaction same with embodiment 26b, obtains the crude product 314mg of filbert solid title compound.The crude product that obtains is directly used in following reaction without making with extra care.
B) 5-cyano group-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate
Use the compound 314mg that obtains among the embodiment 179a, carry out the reaction same, obtain the title compound 331mg (yield 63%, 2 step) of colorless solid with embodiment 36c.194～198 ℃ of fusing points
1H-NMR(DMSO-d 6)：8.13(1H，s)，7.95(1H，d，J＝7.9Hz)，7.84(1H，d，J＝7.7Hz)，7.14-7.07(2H，t，J＝5.6Hz)，6.99(2H，m)，6.59(2H，s)，4.57(2H，s)，4.11(2H，t，J＝5.6Hz)，3.44(2H，d，J＝7.2Hz)，3.06(2H，brd，J＝11.6Hz)，2.87(2H，t，J＝5.5Hz)，2.27(2H，brt，J＝11.0Hz)，1.83-1.77(1H，m)，1.63(2H，brd，J＝11.7Hz)，1.36-1.23(2H，m).
Embodiment 180:5-fluoro-2-[[1-[2-(4-fluorophenoxy) ethyl] piperidin-4-yl] methyl] isoindoline-1-ketone fumarate
Use the compound that obtains among the embodiment 154c, carry out the operation same, obtain title compound (yield 88%) with embodiment 26b, 36c.174～176 ℃ of fusing points
1H-NMR(DMSO-d 6)：δ1.25(m，2H)，1.60(m，2H)，1.76(m，1H)，2.17(m，2H)，2.79(t，J＝5.6Hz，2H)，3.50(m，2H)，3.39(d，J＝7.2Hz，2H)，4.07(t，J＝5.6Hz，2H)，4.47(s，2H)，6.60(s，2H)，6.95(m，2H)，7.10(t，J＝8.9Hz，2H)，7.31(m，1H)，7.46(dd，J＝1.9，8.7Hz，1H)，7.70(dd，J＝5.2，8.3Hz，1H).
Embodiment 181:4-fluoro-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate (compound 212 of table 1)
A) 4-fluoro-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone
Use the compound that obtains among the embodiment 6d (300mg, 1.05mmol) and the compound that obtains among the embodiment 32a (230mg 1.05mmol), carries out the reaction same with embodiment 26b, obtains the crude product 356mg of filbert solid title compound.The crude product that obtains is directly used in following reaction without making with extra care.
B) 4-fluoro-2-[1-[2-(4-fluorophenoxy) ethyl] the piperidin-4-yl methyl] isoindoline-1-ketone fumarate
Use the compound 356mg that obtains among the embodiment 181a, carry out the reaction same, obtain the title compound 412mg (yield 89%, 2 step) of colorless solid with embodiment 36c.196～198 ℃ of fusing points
1H-NMR(DMSO-d 6)：7.56-7.53(2H，m)，7.46(1H，m)，7.13-7.07(2H，m)，6.97-6.92(2H，m)，6.60(2H，s)，4.57(2H，s)，4.07(2H，t，J＝5.7Hz)，3.41(2H，d，J＝7.4Hz)，2.99(2H，brd，J＝11.7Hz)，2.78(2H，t，J＝5.7Hz)，2.16(2H，brt，J＝10.9Hz)，1.80-1.75(1H，m)，1.61(2H，brd，J＝11.6Hz)，1.32-1.23(2H，m).
Embodiment 182:2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride 2 hydrates
To 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-keto hydrochloride (compound of embodiment 1) adds entry (30mL) and acetone (210mL) in (39.4mmol), be heated to 60 ℃ and make its dissolving, after wherein splashing into vinyl acetic monomer (100mL), put and be chilled to room temperature.Filter and collect the crystallization of separating out, after the crystallization of acquisition was washed with vinyl acetic monomer, decompression was dry down, obtains title compound (yield 79%).
Ultimate analysis: (calculated value) C, 60.20; H, 6.43; N, 6.38; Cl, 8.08 (analytical value) C, 60.02; H, 6.24; N, 5.97; Cl, 7.74
Water analysis: (Karl Fischer method) (calculated value) 8.2% (analytical value) 8.3%
The test example: the σ combining site is in conjunction with suppressing experiment
The receptors bind of sigma 2 selective suppresses the carrying out of experiment, as radioligand, use [ 3H]-two-neighbour-tolyl guanidine (DTG, ultimate density lnM, 37Ci/mmol, New EnglandNuclear, Dupont de Nemours).Adopt the method for document record, by the liver of male rat (Sprague-Dawley system) prepare thick P2 film fraction (people such as X.He, " medical chemistry magazine " (J.Med.Chem.), 36, pp.566-571,1993).At the pentazocine of 500nM and the control compound of various concentration (haloperidol (10 -10～10 -6M) or at tested part (10 -10～10 -5M) and under the existence of radioligand, P2 fraction (0.4ml) was cultivated 2 hours in 25 ℃ 50mM Tris-HCl (pH7.4, termination capacity 0.5ml).Use 1 hour Whatman of dipping system GF/B filter paper in 0.5% polymine in advance,, reaction is stopped with the quick filtering reacting liquid of Brandel cell harvestor.Filter paper is washed 4 times with ice-cooled cultivation damping fluid.Non-specific result is to use 1 μ M haloperidol to estimate, and carries out scintillation analysis and tracing analysis as described above.Should illustrate, [ 3H]-the Kd value of DTG is 6.9nM.The results are shown in following table-3 and the table-4.
Table-3
Test compound σ2 Ki(nM)
Embodiment 1 13
Embodiment 2 2.8
Embodiment 3 7
Embodiment 4 7.6
Embodiment 6 8.7
Embodiment 7 16
Embodiment 8 3.1
Embodiment 9 4.9
Embodiment 13 6.6
Embodiment 17 24
Embodiment 22 22
Embodiment 24 13
Embodiment 26 10
Embodiment 30 22
Embodiment 31 22
Embodiment 32 2.8
Embodiment 36 50
Embodiment 50 14
Embodiment 84 3.4
Embodiment 137 7.8
Embodiment 154 16
Embodiment 159 25
Embodiment 160 10
Table-4
Test compound σ 2 inhibiting rates (%, 10nM)
Embodiment 48 59
Embodiment 50 52
Embodiment 51 74
Embodiment 53 57
Embodiment 72 55
Embodiment 76 84
Embodiment 77 80
Embodiment 78 86
Embodiment 84 58
Embodiment 85 59
Embodiment 94 83
Embodiment 95 69
Embodiment 96 66
Embodiment 97 59
Embodiment 109 68
Embodiment 110 68
Embodiment 111 51
Embodiment 112 60
Embodiment 113 64
Embodiment 114 51
Embodiment 117 52
Embodiment 118 50
Embodiment 158 57
Embodiment 167 62
Embodiment 170 52
Embodiment 177 55
Embodiment 178 50
Embodiment 181 70
The prescription example
Medical composition of the present invention can use industry method and formulation commonly used to prepare with additive.The typical case who below the is shown in medicament of the present invention example of writing out a prescription, but medical composition of the present invention is not limited to this.
1) tablet
Compound 0.1～50mg of embodiment 2
Calcium phosphate 20mg
Lactose 30mg
Sliding 10mg
Magnesium Stearate 5mg
Yam starch adds to 200mg
2) suspension agent
Add entry in compound 1～5mg, Xylo-Mucine 50mg, Sodium Benzoate 1mg and the Sorbitol Powder 500mg of embodiment 2, the preparation total amount is the aqueous suspension agent of the oral administration of 1ml.
3) injection
In the mixture of the propylene glycol of 10 volume % and distilled water for injection, stir and be mixed into compound,, prepare composition for injection the solution film filter filtration sterilization that obtains as the embodiment 2 of 1.5 weight % of effective constituent amount.
4) ointment
The compound 1～1 of embodiment 2,000mg
Stearyl alcohol 3g
Lanolin 5g
White Vaseline 15g
Water adds to 100g
Utilize possibility on the industry
Compound of the present invention has high compatibility for the σ binding site. And then compound of the present invention has the good pharmacokinetics distribution maps such as oral absorption is good, accretion rate is little, and its security is good, in the pharmacological testing that uses animal model, has very high drug effect. Thereby compound of the present invention is useful as sigma ligands for treating and/or preventing of the various diseases relevant with sigma ligands and symptom.

Claims (13)

1. the compound or its salt of a formula (I) expression or their hydrate,
Figure C018086870002C1
In the formula,
X represents C1～6 alkyl, C1～6 alkyl that aryl replaces, unsubstituting aromatic yl or C2～6 alkenyls that replaced by the aryl that halogen atom replaces, unsubstituting aromatic yl or C2～6 alkynyls that replaced by the aryl that halogen atom replaces, C3～8 cycloalkyl, replace or unsubstituted C6～14 aryl, replacement or unsubstituted, contain and be selected from Sauerstoffatom, 1～4 heteroatoms of sulphur atom and nitrogen-atoms is as 5～10 element heterocycle bases of ring atom, perhaps replace or unsubstituted amino, wherein, the C6 of above-mentioned replacement～14 aryl, substituting group on 5～10 element heterocycle groups that replace can be halogen atom, nitro, C1～6 alkyl, phenyl C1～6 alkyl, halo C1～6 alkyl, hydroxyl, C1～6 alkoxyl groups, phenyl C1～6 alkoxyl groups, C1～6 alkyl that aryl replaces, halo C1～6 alkoxyl groups, unsubstituted phenyl, the phenyl that halogen atom or C1～6 alkoxyl groups replace, phenoxy group, amino, acyl group, C1～6 alkylaminos, C1～6 alkanoylamino, the substituting group on the amino of described replacement can be C1～6 alkyl, do not replace C6～14 aryl, by C6～14 aryl of halogen atom or C1～6 alkoxyl groups replacement;
Above-mentioned aryl except C6～14 aryl is that atomicity is the aryl of 6～14,1～3 rings, and in addition, for the aryl of 2～3 rings, what the part of ring was hydrogenated is also included within this aryl;
Q is-CO-;
N represents integer 1;
R 1And R 2Represent hydrogen atom or C1～6 alkyl independently of one another;
B represents following radicals:
Figure C018086870002C2
In the formula, R 3, R 4, R 5And R 6Represent the substituting group from hydrogen atom, halogen atom, nitro, C1～6 alkyl, halo C1～6 alkyl, hydroxyl, C1～6 alkoxyl groups, halo C1～6 alkoxyl groups and cyano group, selected independently of one another;
M represents 1 or 2.
2. described compound or its salt of claim 1 or their hydrate, wherein,
X is C1～6 alkyl, aryl replaces C1～6 alkyl, aryl replaces C2～6 alkenyls, aryl replaces C2～6 alkynyls, replace or unsubstituted C6～14 aryl, monocycle C3～8 cycloalkyl, contain and be selected from Sauerstoffatom, 1～4 heteroatoms of sulphur atom and nitrogen-atoms is as 5～10 Yuans monocycle heterocyclic radicals of ring atom, contain and be selected from Sauerstoffatom, sulphur atom and nitrogen-atoms 1 or 2 heteroatomic atomicities are 8～10 two ring property heteroaryls, perhaps use the amino of C1～6 alkyl or C6～14 aryl replacement;
Above-mentioned aryl except C6～14 aryl is that atomicity is the aryl of 6～14,1～3 rings, and in addition, for the aryl of 2～3 rings, what the part of ring was hydrogenated is also included within this aryl;
N is an integer 1;
R 1And R 2Be hydrogen atom;
R 3, R 4, R 5And R 6Be the substituting group of from hydrogen atom, halogen atom, nitro, C1～6 alkyl, halo C1～6 alkyl, hydroxyl, C1～6 alkoxyl groups, halo C1～6 alkoxyl groups and cyano group, selecting independently of one another;
M is 1 or 2.
3. described compound or its salt of claim 2 or their hydrate, wherein,
X is for replacing or unsubstituted phenyl, to contain 1～4 heteroatoms being selected from Sauerstoffatom, sulphur atom and nitrogen-atoms be 5 or 6 monocycle heterocyclic radical as the atomicity of ring atom or contain 1 of being selected from Sauerstoffatom, sulphur atom and nitrogen-atoms or 2 heteroatomic atomicities are 8～10 two ring property heteroaryls, wherein, the substituting group 1 or 2 or more of the substituting group on the phenyl of replacement for from halogen atom, C1～6 alkyl, halo C1～6 alkyl, C1～6 alkoxyl groups and halo C1～6 alkoxyl groups, selecting.
4. described compound or its salt of claim 2 or their hydrate, wherein,
B represents with following formula:
Figure C018086870003C1
In the formula, R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is the substituting group selected from hydrogen atom, halogen atom, nitro, C1～6 alkyl, hydroxyl, C1～6 alkoxyl groups and cyano group.
5. described compound or its salt of claim 1 or their hydrate, wherein,
X is for replacing or unsubstituted phenyl, and wherein substituting group is the substituting group of selecting from halogen atom and C1～6 alkoxyl groups more than 1 or 2;
N is 1;
R 1And R 2Be all hydrogen atom;
R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is hydrogen atom, halogen atom or C1～6 alkoxyl groups;
M is 1 or 2.
6. described compound or its salt of claim 5 or their hydrate, wherein,
X is to fluorophenyl, and n is 1, R 3, R 4, R 5And R 6In 3 be hydrogen atom, remaining one is hydrogen atom, halogen atom or methoxyl group, m is 1.
(7.2-(1-(2-(4-fluorophenyl)-2-oxoethyl) piperidin-4-yl) methyl) isoindoline-1-ketone or its salt or their hydrate.
8.4-fluoro-2-((1-(2-(4-fluorophenyl)-2-oxoethyl) piperidin-4-yl) methyl) isoindoline-1-ketone or its salt or their hydrate.
9.5-chloro-2-((1-(2-(4-fluorophenyl)-2-oxoethyl) piperidin-4-yl) methyl) isoindoline-1-ketone or its salt or their hydrate.
10.5-fluoro-2-[[1-[2-(4-fluorophenyl)-2-oxoethyl] piperidin-4-yl] methyl] isoindoline-1-ketone or its salt or their hydrate.
11. a medicine wherein, contains the material selected in Accessory Right requirement 1～10 each described compound and salt and their hydrate as effective constituent.
12. the described medicine of claim 11, it is used to the disease that the neuroregulation effect by sigma ligands treats and/or prevents.
13. the described medicine of claim 12, wherein, the disease that neuroregulation effect by sigma ligands treats and/or prevents is to be selected from anxiety, melancholia or mood disorders, schizophrenia, lit or narcotic are habit-forming, sharp pain, dyskinesia, cerebrovascular disorder, epilepsy, the dementia that comprises Alzheimer, Parkinsonism, central nervous system disease during cerebral tumor and attention disappearance are hindered, be selected from the big bowel syndrome of supersensitivity, irritable bowel syndrome, spastic colon, the mucous membrane colitis, enterocolitis, gastrointestinal illness in diverticulitis and the dysentery, perhaps be selected from essential hypertension, cardiovascular system diseases in arrhythmia and the stenocardia.
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